Asymmetric synthesis of 2-alkyl-3-thiazoline carboxylates: Stereochemistry of the MnO2-mediated oxidation of cis- and trans-2-alkyl-thiazolidine-(4R)-carboxylates

Article abstract of DOI:10.1016/S0957-4166(01)00219-1

The asymmetric synthesis of a series of 3-thiazoline carboxylates, 2, was effected by MnO₂ oxidation of the corresponding cis/trans thiazolidines, 1. The stereochemistry of the oxidation reaction was studied using NMR and chiral GC analyses. Compounds 2 were obtained with enantiomeric excesses (e.e.s) in the range of 40-100%.

Full text of DOI:10.1016/S0957-4166(01)00219-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1279–1286
Asymmetric synthesis of 2-alkyl-3-thiazoline carboxylates:
stereochemistry of the MnO2-mediated oxidation of cis- and
trans-2-alkyl-thiazolidine-(4R)-carboxylates
Xavier Fernandez and Elisabet Dun˜ach*
Laboratoire Aroˆmes, Synthe`ses et Interactions, Universite´ de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice Cedex 2, France
Received 2 April 2001; accepted 14 May 2001
Abstract—The asymmetric synthesis of a series of 3-thiazoline carboxylates, 2, was effected by MnO2 oxidation of the
corresponding cis/trans thiazolidines, 1. The stereochemistry of the oxidation reaction was studied using NMR and chiral GC
analyses. Compounds 2 were obtained with enantiomeric excesses (e.e.s) in the range of 40–100%. © 2001 Elsevier Science Ltd.
All rights reserved.
1. Introduction
ratios in the range of 1/1–19/1. However, the reaction
was efficient only with bulky aldehydes and high
diastereoisomeric ratios were obtained only with very
bulky substituents.
Alkyl thiazolines are widely studied in food and flavor-
ings chemistry.1 More than 30 thiazoline structures
have now been identified from natural sources and
foods,2 particularly in cooked meat1,3 and in certain
exotic fruit such as lychees.4 There has also been con-
siderable industrial interest related to these compounds,
due to their ability to enhance the flavor and/or aroma
of various consumable materials, including foodstuffs.5
We recently proposed a novel strategy for the synthesis
of 4-carboxy-2-substituted 3-thiazolines of the type 2,
parallel to the biosynthetic route, in which thiazolidines
were selectively oxidized to 3-thiazolines by MnO2
(Scheme 3).8 The obtained heterocycles contain a
stereogenic center at C(2). In the study presented
herein, we focus on the asymmetric synthesis of the
3-thiazolines 2. Analysis of the 3-thiazoline products by
NMR and chiral GC showed that e.e.s in the range of
40–100% were obtained.
The preparation of 3-thiazolines has been reported
through the Asinger reaction,6 a multi-component pro-
cess between an a-mercaptoketone, an aldehyde and
ammonia. Recently, Martens et al.7 proposed the only
reported example of asymmetric synthesis of 3-thiazol-
ines by a modified Asinger procedure, using in combi-
nation with an a-chloro-substituted aldehyde or ketone,
aqueous ammonia, sodium hydrogenosulfide and a sec-
ond homochiral aldehyde. 3-Thiazolines were obtained
in yields of between 27 and 85% with diastereoisomeric
2. Results and discussion
Thiazolidines, 1a–1l, were easily obtained in yields of
80–95% from the condensation of
L- or (R)-cysteine
Scheme 1. Thiazolidine synthesis.
* Corresponding author. Fax: 33(0) 492076121; e-mail: dunach@unice.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00219-1

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X. Fernandez, E. Dun˜ach / Tetrahedron: Asymmetry 12 (2001) 1279–1286
The oxidation of methyl or ethyl 2-alkyl-thiazolidine-
4(R)-carboxylates, 1/1%, with an excess of MnO2 in
CH3CN at 50°C led to a mixture of 3-thiazolines 2a–2l
and thiazole 3 (Scheme 3). After column purification,
3-thiazolines were obtained in moderate to good yields
(Table 3). Apart from our studies, these series of hete-
rocycles, 2a–2l, possessing an ester substituent at the
4-position have not, to our knowledge, been described.
Upon oxidation compounds 2 lost the C(4) stereogenic
center, but present a stereogenic center at C(2).
Although we initially expected e.e.s of 2 to be in the
same range as the cis/trans ratios obtained for 1/1%
mixtures, the e.e.s of compounds 2 were found to be
much higher in most cases. The e.e.s were measured by
1H NMR, by the use of the chiral shift reagent, tris-
[3(trifluoromethylhydroxymethylene)-(+)-camphorato]-
europium(III), Eu(tfc)3 (Table 3). In all cases, a shift
and a good separation of the C(2)H protons occurred,
the separation being around 0.15–0.25 ppm. The e.e.s
were also determined by chiral GC using Chiraldex
B-PH as the column. The results obtained by chiral GC
were comparable ( 5%) to those obtained by NMR.
ethyl or methyl esters (or their ammonium salts) and an
alkyl aldehyde derivative under slightly basic
conditions9,10 (Scheme 1, Table 1). This condensation
afforded 1 as a mixture of diastereomers, cis-(2R,4R)-1
and trans-(2S,4R)-1% (Scheme 1), which could not be
separated. An equilibrium resulting from epimerization
at C(2) occurs between 1 and 1% (Scheme 2).11
1
The H NMR of the mixture of the two isomers 1 and
1% was studied. NMR proved to be the best method of
analysis; the spectra of the cis/trans isomers showed
distinct signals for the two isomers, and the C(2) pro-
tons were well resolved in all of the spectra obtained.
We performed 2D NOESY experiments to determine
the absolute configuration of the C(2) center, which
showed a C(4)H to C(2)H correlation which was ade-
quate for determining the cis/trans configuration. The
major isomer presented an interaction between C(2)H
and C(4)H, while the C(4)H proton was correlated with
C(5)H in the minor isomer. The space-proximity of the
C(2)H and C(4)H protons gave evidence for a cis
configuration of the ester and R2 groups in the main
isomer 1. The absolute configuration of C(4), deter-
mined by the starting material, was (R) and the abso-
lute configuration of C(2) was also (R) for the cis
isomer. In all of the cases examined (Table 1), the cis
isomers predominated in CDCl3 at room temperature.
Table 2. Variation of the cis/trans ratios of ethyl 2-ethyl-
thiazolidine-(4R)-carboxylate, 1/1%h, as a function of the
solvent, at 20°C
Solvent
Ratio cis/trans (%)
The cis/trans ratios were not dependent on the temper-
ature; however, they were strongly dependent on the
nature of the solvent (Table 2). In CDCl3, CD3OD and
CD3CN, the major isomer for 1/1%h was the cis isomer.
However, in DMSO-d6, the trans diastereoisomer pre-
dominated after complete equilibration.
CDCl3
67/33
52/48
6/4
CD3OD
CD3CN
DMSO-d6
46/54
Table 1. Synthesis of thiazolidines 1/1%
Entry
Compound 1/1%
R1
R2
Isolated yield of 1/1% (%)
Ratio cis/transc (%)
1
2
3
4
5
6
7
8
1/1%a
1/1%b
1/1%c
1/1%d
1/1%e
1/1%f
1/1%g
1/1%h
1/1%i
1/1%j
1/1%k
1/1%l
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
i-Pr
i-Pr
Me
Et
90a
89a
82a
94a
90b
93a
93a
90a
92a
89b
90b
89b
61/39
62/38
68/32
70/30
69/31
71/29
71/29
67/33
69/31
69/31
69/31
62/38
n-Pr
i-Pr
n-Bu
i-Bu
Me
Et
9
n-Pr
n-Bu
Et
10
11
12
i-Pr
a Compounds obtained by condensation of
L-cysteine ethyl or methyl esters and aldehydes.
b Compounds obtained by esterification of the corresponding thiazolidine-(4R)-carboxylic acids.
c Ratios determined by 1H NMR, in CDCl3 at 20°C.
Scheme 2. Thiazolidine epimerization.

X. Fernandez, E. Dun˜ach / Tetrahedron: Asymmetry 12 (2001) 1279–1286
1281
Scheme 3. MnO2-mediated oxidation of thiazolidines 1/1%a–l.
Table 3. MnO2-mediated oxidation of thiazolidines 1/1%
tated MnO2 hydrate (Prolabo) and MnO2 suitable for
use in batteries (Aldrich) gave the best yields. MnO2
obtained by
afforded a much lower yield of 2, and MnO2 powder
(Acros) led to very low oxidation efficiencies. Even
though MnO2 hydrate and battery grade MnO2 were
comparable in conversion efficiencies, they did not
afford the same asymmetric control. The oxidation of 1
Steric hindrance at C(2) and C(4) appears to be impor-
tant to the stereochemical outcome of the reaction and
affected the e.e. value of the product markedly (entries
13 and 14).
a
modified Attenburrow procedure12
We observed that the MnO2 source also had a marked
influence on the stereoselectivity of this heterogeneous
process. Several grades of MnO2 were tested: Precipi-

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X. Fernandez, E. Dun˜ach / Tetrahedron: Asymmetry 12 (2001) 1279–1286
with MnO2 hydrate (method A) led to 3-thiazolines
with widely variable e.e.s in the range 2–83% as shown
in Table 3. In contrast, method B using battery grade
MnO2 gave good, reproducible results, with e.e.s in the
range 73–100% (except for entry 14). For the two
methods, comparing entries 3, 8, 4 and 11 the e.e.
differences are considerable. Thus, in the case of ethyl
2-methyl-3-thiazoline-4-carboxylate, the e.e. was 2%
with MnO2 hydrate, but increased to 73% by the use of
the battery grade MnO2 as oxidant. Previous reports
have also indicated that the structure and reactivity of
active manganese dioxide used as an oxidizing agent in
organic synthesis was strongly dependent on the
method of its preparation.13,14 The differences in asym-
metric induction obtained in the oxidation of 1/1% to 2
emphasize the importance of the grade of MnO2 used.
2b was formed, and only the corresponding thiazole 3b
could be isolated. We also prepared the proposed inter-
mediate 4b by condensing
L-cysteine ethyl ester with
ethyl acetimidate.16 Here again, oxidation with different
quantities of MnO2 (3–10 equiv.) led to thiazole 3b in
all cases. These observations indicate that the isomer-
ization from 2-thiazolines to 3-thiazolines does not take
place under the reaction conditions. Therefore, mecha-
nism I can be excluded. To further eliminate this path-
way I, the MnO2-mediated oxidation of a 2,2-dialkyl-
substituted thiazolidine-(4R)-carboxylate was carried
out. However, the reaction led to decomposition of the
heterocycle and no mechanistic considerations could be
concluded from the experiment.
According to these experimental data, only mechanism
II seems plausible. A dynamic process involving equili-
bration between 1 and 1% under the reaction conditions,
with one diastereoisomer reacting at a faster rate than
the other, could account for the enhanced enantioselec-
tivity of the products relative to the initial diastereoiso-
meric mixture.
A series of racemic ethyl or methyl thiazolidine-(4RS)-
carboxylates ( )-1/1% were oxidized with battery grade
MnO2 (method B). Compounds 1b/1%b, 1h/1%h and 1i/1%i
were obtained by reaction of DL-cysteine with alkyl
aldehydes, followed by esterification of the carboxylic
acid function. The obtained 3-thiazolines, 2b, 2h and 2i,
1
had e.e.s in the range of 1–4% according to H NMR
Precise elucidation of the mechanism of oxidation by
manganese dioxide is difficult because of the nature of
the heterogeneous reaction involved. The difficulties
encountered in studying these reactions result from the
structure of the oxidant, particularly the relationship of
its surface-active sites toward the substrate and its
stereoelectronic factors. Previous studies on the oxida-
tion mechanism by MnO2 suggested the presence of an
adsorptive process.13 The reaction pathway involves
adsorption of the substrate onto the surface of the
oxide, followed by its radical-type oxidation and de-
sorption of the product. Accordingly, we present in
Scheme 5 a plausible oxidation mechanism involving
Mn(IV) and Mn(III) species. The adsorption of 1/1%
onto the MnO2 surface occurs with an NꢀMn(IV)-coor-
dination. The further coordination of ester to the Mn
species should enhance the stability of the intermediate
diastereomer in which the R2 substituent at C(2) has
trans (or (S)) configuration. The oxidative electron
transfer with the intermediate formation of an Mn(III)/
analysis in the presence of Eu(tfc)3.
Two possible mechanisms can be considered to explain
the asymmetric induction from 1/1% to 2. In the first
mechanism, I (Scheme 4), a first oxidation of thiazo-
lidine 1/1% to a homochiral 2-thiazoline intermediate 4
can be considered, followed by isomerization of 4 with
chirality transfer to 3-thiazoline 2. The second mecha-
nism II (Scheme 4) involves the direct NꢀC(4) oxidation
of the 1/1% to 3-thiazoline 2. In this case, to explain the
high asymmetric induction found for 2, we have to
consider a fast equilibrium between 1 and 1%, and
enhanced reactivity of one of the diastereomers 1 or 1%.
In order to differentiate between the possible pathways
I and II, several experiments were carried out. To check
the possibility of mechanism I, we prepared 2-thiazol-
ines 4 by an Ru-catalyzed/TBHP oxidation of 1/1%,
which occurred with good regioselectivities (>95%).15 In
particular, ethyl 2-methyl-2-thiazoline-(4R)-carboxylate
4b (R1=Et and R2=Me) was prepared in 36% yield
and treated with MnO2 under the same reaction condi-
tions as those of Table 3 (method B). No 3-thiazoline
’
N-centered radical species loses H to give the imine–
Mn(II) complex. Desorption then affords the product
Scheme 4. Oxidation pathways.

X. Fernandez, E. Dun˜ach / Tetrahedron: Asymmetry 12 (2001) 1279–1286
1283
Scheme 5. Proposed mechanism.
2, in which the stereogenic center at C(2) is proposed to
have (S) configuration. The e.e.s of the different 3-thia-
zolines were measured, but the absolute configurations
are not known at this time.
Chromatographic separations were performed using
70–260 mesh (SDS) silica gel eluted with mixed solvent
of hexane and ether by changing the ratios from 9/1 to
4/1, 7/3 and finally to 6/4. Thin-layer chromatography
was carried out on SDS precoated silica plates (60/15
mm layer thickness).
3. Conclusion
4.2. Thiazolidine synthesis
We have presented a new and practical asymmetric
synthesis of alkyl 3-thiazoline-4-carboxylates 2 with
high e.e.s by MnO2-mediated oxidation of the corre-
sponding chiral thiazolidines 1/1%. The asymmetric
induction was strongly dependent upon the source of
the manganese dioxide. The use of MnO2 suitable for
use in batteries (Aldrich) led to the best results with
high e.e. For several alkyl substituents, the e.e.s lie in
the range 73–100%. MnO2 coordination to the ester
and the amine groups of 1/1% can be considered, fol-
lowed by the direct selective NꢀC(4) dehydrogenation
to 2. The coordination of MnO2 to either 1 or 1% occurs
with high diastereoselectivity under kinetic control.
4.2.1. Condensation of
L
-cysteine ethyl or methyl ester
-cysteine ethyl
with aldehydes. To a stirred solution of
L
ester hydrochloride (10 mmol) and potassium acetate
(0.98 g, 10 mmol) in alcohol (30 mL), a solution of
freshly distilled aldehyde in alcohol (10 mL) was added
at 0°C. After stirring for 4 h at 0°C, the reaction
mixture was filtered off and the solvent evaporated
under reduced pressure. The crude product was washed
with a saturated solution of aqueous NaCl (15 mL) and
extracted three times with CH2Cl2 (3×15 mL). The
organic phase was dried over MgSO4 and the solvent
evaporated. A colorless oil was obtained.
4.2.2. Esterification of thiazolidine-(4R)-carboxylic acids.
Thiazolidine-(4R)-carboxylic acids were obtained by
4. Experimental
4.1. General
the reaction of
L-cysteine with aldehydes using the
method of Schubert.17 To a stirred solution of 2-substi-
tuted thiazolidine-(4R)-carboxylic acid (0.1 mol) in
absolute alcohol (methanol, ethanol or iso-propanol)
was added thionyl chloride in small portions at 0°C.
The mixture was stirred at room temperature for 12 h
and stirred under reflux for 1 h. The reaction mixture
was filtered and the solvent evaporated under reduced
pressure. The crude product was dissolved in H2O,
neutralized with a saturated solution of aqueous K2CO3
and extracted three times with CH2Cl2 (3×20 mL). The
organic phase was dried over MgSO4 and the solvent
evaporated. A colorless oil was obtained. Experimental
and spectroscopic data for compounds 1/1% have
already been reported.18,19 However, the relative posi-
tions of the different protons in 1H NMR for the
cis/trans isomers have not been fully described. We
All solvents and reagents were purchased from com-
mercial suppliers and used as received unless otherwise
1
indicated. H and 13C NMR data were recorded on a
Bruker AC 200 FT spectrometer, at room temperature,
with 40 mg of product in 0.5 mL CDCl3 and TMS as
1
internal standard. 2D H NMR spectra were recorded
on a Bruker AMX 400 spectrometer. Acquisition and
processing parameters for NOESY experiments: data
points in F1: 256 and F2: 1024, mixing time: 1–2 s, zero
filling: 1024. Chemical shifts are reported in l ppm.
GC analysis was carried out using an HP-5890 gas
chromatograph. GC–MS analysis was accomplished by
using an HP-5890 chromatograph coupled to a 5970A
mass selective detector. Mass spectra were obtained by
electron ionization at 70 eV and source temperature of
250°C. High resolution mass spectra (HRMS) were
1
therefore only give here the detailed H NMR spectra
of these compounds.
4.2.3. Methyl 2-methyl-thiazolidine-(4R)-carboxylates
1a/1%a. 1H NMR: l 1.5 (d, 3H, CH3trans, J=6.3 Hz), 1.6
(d, 3H, CH3cis, J=6.2 Hz), 2.2 (s, 2H, N-Hcis and trans),
measured
on
a
Fisons-FG-prospec
magnetic
spectrometer.

1284
X. Fernandez, E. Dun˜ach / Tetrahedron: Asymmetry 12 (2001) 1279–1286
2.9 (td, 1H, H-5cis, J=0.8 and 9.5 Hz), 3.1 (dd, 1H,
H-5trans, J=6 and 10.7 Hz), 3.3 (m, 2H, H-5%cis and trans),
3.7 (2s, 6H, OCH3cis and trans), 3.85 (1H, H-4cis), 4.2 (t,
1H, H-4trans, J=6.6 Hz), 4.5 (q, 1H, H-2cis, J=6.2 Hz),
4.75 (q, 1H, H-2trans, J=6.3 Hz).
(dd, 3H, CH3trans, J=1.1 and 6.3 Hz), 1.6 (dd, 3H,
CH3cis, J=0.9 and 6.1 Hz), 2.9 (td, 1H, H-5cis, J=1.2
and 9.5 Hz), 3.1 (dd, 1H, H-5trans, J=6.1 and 10.7 Hz),
3.3 (m, 2H, H-5%
trans), 3.8 (t, 1H, H-4cis, J=7.2
Hz), 4.2 (m, 8H,cisOaCndH2CH3cis
trans, H-4trans, N-Hcis
and
and trans), 4.55 (qd, 1H, H-2cis, J=1.1 and 6.2 Hz), 4.8
(q, 1H, H-2trans, J=6.4 Hz).
4.2.4. Methyl 2-ethyl-thiazolidine-(4R)-carboxylates 1b/
1
1%b. H NMR: l 0.95 (t, 3H, CH2CH3trans, J=7.4 Hz),
1 (3H, t, CH2CH3cis, J=7.4 Hz), 1.6, 1.7 and 1.9 (3m,
4H, CH2CH3cis and trans), 2.2 (s, 2H, N-Hcis and trans), 2.8
(t, 1H, H-5cis, J=10 Hz), 3 (dd, 1H, H-5trans, J=6.4 and
4.2.10. Ethyl 2-ethyl-thiazolidine-(4R)-carboxylates 1h/
1
1%h. H NMR: l 0.95 (t, 3H, CH2CH3trans, J=7.4 Hz),
1 (t, 3H, CH2CH3cis, J=7.4 Hz), 1.25 (6H, 2t,
OCH2CH3cis and trans), 1.8 (2m, 2H, CH2CH3cis and trans),
2.6 (m, 2H, N-Hcis and trans), 2.8 (dd, 1H, H-5cis, J=1.2
10.6 Hz), 3.2 (m, 2H, H-5%
trans), 3.7 (s, 3H,
cis and
OCH3cis), 3.75 (s, 3H, OCH3trans), 3.8 (dd, 1H, H-4cis,
J=6.4 and 9.6 Hz), 4.1 (t, 1H, H-4trans, J=6.6 Hz), 4.4
(dd, 1H, H-2cis, J=5.7 and 7 Hz), 4.55 (dd, 1H, H-
2trans, J=6 and 7.6 Hz).
and 9.5 Hz), 2.95 (dd, 1H, H-5trans), 3.2 (m, 2H, H-5%
cis
and trans), 3.75 (1H, dd, H-4cis, J=7.1 and 9.3 Hz), 4.05
(t, 1H, H-4trans, J=6.6 Hz), 4.15 (m, 4H, OCH2CH3cis
and trans), 4.4 (1H, dd, H-2cis, J=5.5 and 6.4 Hz), 4.55
(dd, 1H, H-2trans, J=6 and 7.7 Hz).
4.2.5. Methyl 2-propyl-thiazolidine-(4R)-carboxylates
1
1c/1%c. H NMR: l 0.85 (t, 3H, (CH2)2CH3trans, J=7.2
Hz), 0.9 (t, 3H, (CH2)2CH3cis, J=7.2 Hz), 1.4, 1.55, 1.7
and 1.85 (4m, 8H, CH2CH2CH3cis and trans), 2.2 (s, 2H,
4.2.11. Ethyl 2-propyl-thiazolidine-(4R)-carboxylates 1i/
1
1%i. H NMR: l 0.9 (t, 6H, (CH2)2CH3cis and trans, J=7.2
N-Hcis
trans), 2.8 (dd, 1H, H-5cis, J=9.5 and 10.1
Hz), 1.2 (2t, 6H, OCH2CH3cis and trans, J=7.2 Hz), 1.4
and 1.6 (2m, 2H, CH2CH2CH3cis and trans), 1.7 and 1.9
(2m, 2H, CH2CH2CH3cis and trans), 2.2 (s, 2H, N-Hcis and
trans), 2.7 (t, 1H, H-5cis, J=9.8 Hz), 2.9 (dd, 1H, H-
and
Hz), 3 (dd, 1H, H-5trans, J=6.2 and 10.6 Hz), 3.2 (m,
2H, H-5%cis and trans), 3.7 (s, 3H, OCH3trans), 3.72 (s, 3H,
OCH3cis), 3.8 (dd, 1H, H-4cis), 4,1 (t, 1H, H-4trans
,
J=6.6 Hz), 4,45 (dd, 1H, H-2cis, J=5.7 and 7.2 Hz), 4.6
(dd, 1H, H-2trans, J=5.7 and 7.2 Hz).
5
trans, J=6.5 and 10.6 Hz), 3.2 (m, 2H, H-5%cis and trans),
3.7 (dd, 1H, H-4cis, J=7 and 9.4 Hz), 4 (t, 1H, H-4trans
J=6.7 Hz), 4.15 (m, 4H, OCH2CH3cis and trans), 4.4 (dd,
,
4.2.6. Methyl 2-isopropyl-thiazolidine-(4R)-carboxylates
1d/1%d. 1H NMR: l 0.9, 0.95, 1 and 1.05 (4d, 12H,
CH(CH3)2cis and trans, J=6.2 Hz, 6.7 Hz, 6.7 Hz, 6.6 Hz),
1.75 (octuplet, 1H, CH(CH3)2trans, J=6.7 Hz), 1.9
(octuplet, 1H, CH(CH3)2cis, J=6.7 Hz), 2.2 (s, 2H,
N-Hcis and trans), 2.7 (t, 1H, H-5cis, J=9.8 Hz), 2.95 (dd,
1H, H-2cis, J=5.7 and 7.2 Hz), 4.6 (t, 1H, H-2trans
J=6.8 Hz).
,
4.2.12. Ethyl 2-butyl-thiazolidine-(4R)-carboxylates 1j/
1
1%j. H NMR: l 0.9 (2t, 12H, (CH2)3CH3cis and trans), 1.3
(2t, 3H, OCH2CH3cis and trans, J=7.2 Hz), 1.5, 1.8 and 2
(3m, 12H, (CH2)3CH3cis and trans), 2.3 (s, 2H, N-Hcis and
trans), 2.85 (dd, 1H, H-5cis, J=9.5 and 10.2 Hz), 3.1 (dd,
1H, H-5trans, J=6.5 and 10.6 Hz), 3.3 (m, 2H, H-5%), 3.8
1H, H-5trans, J=6.2 and 10.6 Hz), 3.1 (dd, 1H, H-5trans
,
J=6.7 and 10.6 Hz), 3.2 (dd, 1H, H-5% , J=6.9 and
cis
10.6 Hz), 3.7 (s, 3H, OCH3trans), 3.75 (3H, OCH3cis), 3.8
(dd, 1H, H-4cis), 4.05 (t, 1H, H-4trans, J=6.4 Hz), 4.3 (d,
1H, H-2cis, J=7.2 Hz), 4.45 (d, 1H, H-2trans, J=7.7
Hz).
(dd, 1H, H-4cis, J=7 and 9.4 Hz), 4.1 (t, 1H, H-4trans
J=6.7 Hz), 4.25 (m, 4H, OCH2CH3cis and trans), 4.5 (dd,
1H, H-2cis, J=5.7 and 7.2 Hz), 4.65 (dd, 1H, H-2trans).
,
4.2.7. Methyl 2-butyl-thiazolidine-(4R)-carboxylates 1e/
4.2.13. Isopropyl 2-ethyl-thiazolidine-(4R)-carboxylates
1
1
1%e. H NMR: l 0.9 (2t, 6H, (CH2)2CH3cis and trans), 1.4,
1k/1%k. H NMR: l 0.95 (t, 3H, CH2CH3trans, J=7.2),
1.8 and 2 (3m, 12H, (CH2)2CH3cis and trans), 2.3 (s, 2H,
1.05 (t, 3H, CH2CH3cis, J=7.5 Hz), 1.25 (2d, 12H,
OCH(CH3)2cis and trans, J=2.2 Hz), 1.6, 1.8 and 2 (3m,
4H, CH2CH3cis and trans), 2.5 (2s, 2H, N-Hcis and trans), 2.8
(t, 1H, H-5cis, J=9.7 Hz), 2.95 (dd, 1H, H-5trans, J=6.9
and 10.5 Hz), 3.3 (m, 2H, H-5%cis and trans), 3.8 (dd, 1H,
H-4cis, J=7 and 9.4 Hz), 4 (t, 1H, H-4trans, J=6.9 Hz),
4.45 (dd, 1H, H-2cis, J=5.8 and 7.5 Hz), 4.6 (dd, 1H,
H-2trans, J=6.5 and 7.2 Hz), 5.1 (m, 2H, CH(CH3)2cis
and trans).
N-Hcis
trans), 2.8 (dd, 1H, H-5cis, J=9.5 and 10.3
and
Hz), 3.05 (dd, 1H, H-5trans, J=6.3 and 10.6 Hz), 3.3 (m,
2H, H-5%cis and trans), 3.8 (2s, 6H, OCH3cis and trans), 3.85
(dd, 1H, H-4cis, J=7 and 10.1 Hz), 4.15 (t, 1H, H-4trans
,
J=6.6 Hz), 4.5 (dd, 1H, H-2cis, J=5.7 and 7.2 Hz), 4.65
(dd, 1H, H-2trans, J=5.7 and 7.4 Hz).
4.2.8. Methyl 2-isobutyl-thiazolidine-(4R)-carboxylates
1
1f/1%f. H NMR: l 1 (4d, 12H, CH2CHCH3cis and trans),
1.8 (m, 6H, CH2CHCH3cis and trans), 2.25 (s, 2H, N-Hcis
and trans), 2.85 (dd, 1H, H-5cis, J=9.4 and 10.2 Hz), 3.1
(dd, 1H, H-5trans, J=6.1 and 10.7 Hz), 3.3 (m, 2H,
4.2.14. Isopropyl 2-isopropyl-thiazolidine-(4R)-carboxy-
1
lates 1l/1%l. H NMR: l 0.95 (2d, 12H, CH(CH3)2cis and
trans, J=7 Hz), 1.22 (d, 12H, OCH(CH3)2cis and trans), 1.6
H-5cis
trans), 3.7 (s, 6H, OCH3trans), 3.75 (s, 3H,
(m, 2H, CH(CH3)2cis
trans), 2.5 (2s, 2H, N-Hcis
and
OCH3cis), 3.8 (dd, 1H, H-4cis), 4.15 (t, 1H, H-4trans
J=6.2 Hz), 4.5 (dd, 1H, H-2cis), 4.75 (dd, 1H, H-2trans
J=6.2 and 7.6 Hz).
,
,
trans), 2.75 (t, 1H, Ha-n5dcis, J=9.5 Hz), 2.9 (dd, 1aHnd,
H-5trans, J=6.7 and 10.5 Hz), 3.2 (m, 2H, H-5%
trans), 3.7 (dd, 1H, H-4cis, J=7.1 and 7.3 Hz), 4 (t, 1aHnd,
H-4trans, J=6.8 Hz), 4.5 (dd, 1H, H-2cis, J=5.7 and 7.3
Hz), 4.6 (dd, 1H, H-2trans, J=6.5 and 7.2 Hz), 5.05 (m,
2H, CH(CH3)2cis and trans).
cis
4.2.9. Ethyl 2-methyl-thiazolidine-(4R)-carboxylates 1g/
1
1%g. H NMR: l 1.3 (2t, 6H, OCH2CH3cis and trans), 1.5

X. Fernandez, E. Dun˜ach / Tetrahedron: Asymmetry 12 (2001) 1279–1286
1285
4.3. Synthesis of 3-thiazolines
(58.7), 54 (15.8), 45 (21.8), 42 (23.1), 41 (42.8). HRMS
calcd for C9H15O2NS: 201.0823. Observed: 201.0821.
A mixture of cis- and trans-thiazolidines 1/1% (5 mmol)
was stirred in CH3CN (50 mL) in the presence of
MnO2 (Prolabo, 20 equiv. or Aldrich, 15 equiv.). The
reaction was followed by GC or TLC. The crude
mixture was filtered over Celite. Solvent evaporation
was followed by purification by column chromatogra-
phy on silica gel, with hexane–ether mixture as the
eluent.
4.3.6. Methyl 2-isobutyl-3-thiazoline-4-carboxylate 2f.
1H NMR: l 1 (2d, 6H, (CH2(CH3)2, J=6.6 and 6.8
Hz), 1.6, 1.75 and 2.1 (3m, 3H, CH2CH (CH3)2), 3.9
(s, 3H, OCH3), 4.2 (m, 2H, H-5), 5.8 (m, 1H, H-2).
13C NMR: l 13.86, 22.31, 28.37, 38.06, 42.34, 53.11,
84.32, 161.66, 162.08. GC–MS: 201 (M+, 15.1), 169
(11.5), 168 (100), 154 (22.7), 113 (22.9), 112 (60.5), 108
(19.4), 84 (16.5), 45 (12), 42 (14.9), 41 (24.8).
4.3.1. Methyl 2-methyl-3-thiazoline-4-carboxylate 2a.
1H NMR: l 1.7 (d, 3H, CH3, J=7.6 Hz), 3.9 (s, 3H,
OCH3), 4.2 (dd, 2H, H-5 and H-5%, J=0.4 and 14 Hz),
5.9 (m, 1H, H-2). 13C NMR: l 24.96, 43.33, 53.33,
79.06, 161.83, 162.16. GC–MS: 159 (M+, 43.6), 144
(88.2), 126 (13.6), 112 (100), 100 (19.6), 98 (15), 74
(15.6), 68 (21.4), 59 (46.8), 58 (15), 45 (23.9), 42 (21.1),
41 (14.9). HRMS calcd for C6H9O2NS: 159.0354.
Observed: 159.0350.
1
4.3.7. Ethyl 2-methyl-3-thiazoline-4-carboxylate 2g. H
NMR: l 1.4 (t, 3H, OCH2CH3, J=7.1 Hz), 1.7 (d,
3H, CH3, J=6.7 Hz), 4.25 (2d, 2H, H-5 and H-5%,
J=4.1 and 5.9 Hz), 4.4 (q, 2H, OCH2CH3, J=7.1
Hz), 5.8 (m, 1H, H-2). 13C NMR: l 14.11, 24.84,
45.22, 62.55, 78.98, 161.64, 162.01. GC–MS: 173 (M+,
28.6), 158 (72.4), 130 (15.8), 112 (100), 100 (15.9), 74
(16.5), 73 (13.2), 68 (18.8), 59 (17.3), 55 (15), 45 (18.5),
41 (12.6).
1
4.3.8. Ethyl 2-ethyl-3-thiazoline-4-carboxylate 2h. 1H
NMR: l 1 (t, 3H, OCH2CH3, J=7.2 Hz), 1.35 (td,
3H, CH2CH3, J=0.6 and 7.2 Hz), 1.8 and 2.1 (2m,
2H, CH2CH3), 4.15 (m, 2H, H-5 and H-5%), 4.35 (q,
2H, OCH2CH3, J=7.2 Hz), 5.8 (m, 1H, H-2). 13C
NMR: l 10.47, 14.22, 31.39, 42.59, 62.63, 87.78,
161.79, 162.79. GC–MS: 187 (M+, 28.7), 130 (14.6),
114 (24.7), 113 (13.9), 112 (100), 87 (12), 86 (35.8), 82
(11.3), 68 (14.6), 59 (12.6), 57 (11), 54 (13), 45 (17.3),
41 (27.3). HRMS calcd for C8H13O2NS: 187.0667.
Observed: 187.0667.
4.3.2. Methyl 2-ethyl-3-thiazoline-4-carboxylate 2b. H
NMR: l 1 (t, 3H, CH2CH3, J=7.4 Hz), 1.9 and 2.1
(2m, 2H, CH2CH3), 3.9 (s, 3H, OCH3), 4.2 (m, 2H,
H-5 and H-5%), 5.85 (m, 1H, H-2). 13C NMR: l 10.48,
31.39, 42.56, 53.29, 85.74, 162, 162.19. GC–MS: 173
(M+, 45), 144 (66), 114 (23.9), 113 (14.7), 112 (100),
100 (11.7), 73 (10.3), 68 (17.1), 59 (52.1), 46 (10.2), 45
(21.6), 42 (18.6), 41 (26.7).
1
4.3.3. Methyl 2-propyl-3-thiazoline-4-carboxylate 2c. H
NMR: l 0.9 (t, 3H, (CH2)2CH3, J=7.1 Hz), 1.5 (m,
2H, CH2CH2CH3), 1.75 and 2.1 (2m, 2H,
CH2CH2CH3), 3.9 (s, 3H, OCH3), 4.1 (d, 1H, H-5,
J=1.7 Hz), 4.12 (d, 1H, H-5, J=2.8 Hz), 5.8 (m, 1H,
H-2). 13C NMR: l 13.82, 19.70, 40.57, 42.49, 53.27,
84.22, 161.83, 162.22. GC–MS: 187 (M+, 31.4), 154
(34.7), 144 (23.2), 140 (37.4), 113 (24.5), 112 (100), 84
(20.7), 59 (54), 55 (18.4), 54 (16.3), 45 (23.8), 49 (19.4).
HRMS calcd for C8H13O2NS: 187.0667. Observed:
187.0665.
4.3.9. Ethyl 2-propyl-3-thiazoline-4-carboxylate 2i. 1H
NMR: l 0.9 (t, 3H, (CH2)2CH3, J=7.3), 1.35 (t, 3H,
OCH2CH3, J=7.2 Hz), 1.5 (m, 2H, CH2CH2CH3),
1.75 and 2.1 (2m, 2H, CH2CH2CH3), 4.15 (2d, 2H,
H-5 and H-5%, J=1.8 and 2.9 Hz), 4.35 (q, 2H,
OCH2CH3, J=7.1 Hz), 5.85 (m, 1H, H-2). 13C NMR:
l 13.80, 14.22, 19.70, 40.58, 42.49, 62.59, 84.24,
161.79, 162.12. GC–MS: 201 (M+, 28.6), 168 (33.3),
158 (29.1), 154 (33.9), 130 (15.2), 128 (32.7), 126
(17.7), 113 (25.1), 112 (100), 98 (13.9), 94 (12.8), 86
(42.9), 82 (20.9), 59 (14.7), 55 (19.8), 54 (20.2), 45
(17.4), 41 (15). HRMS calcd for C9H15O2NS:
201.0823. Observed: 201.0837.
4.3.4. Methyl 2-isopropyl-3-thiazoline-4-carboxylate 2d.
1H NMR: l 0.9 and 1.05 (2d, 6H, CH(CH3)2, J=6.6
and 6.8 Hz), 2.3 (m, 1H, CH(CH3)2), 3.9 (s, 3H,
OCH3), 4.1 (t, 1H, H-5, J=1.1 Hz), 4.1 (d, 1H, H-5,
J=1 Hz), 5.8 (m, 1H, H-2). 13C NMR: l 17.54, 19.83,
34.92, 42.38, 53.26, 91.01, 162.01, 162.23. GC–MS:
187 (M+, 28.4), 145 (43.4), 144 (11.6), 113 (100), 112
(42.4), 85 (16.6), 59 (33), 55 (11.7), 45 (12.5), 41 (14.9).
HRMS calcd for C8H13O2NS: 187.0667. Observed:
187.0656.
4.3.10. Ethyl 2-butyl-3-thiazoline-4-carboxylate 2j. 1H
NMR: l 0.9 (t, 3H, (CH2)3CH3, J=7 Hz), 1.4 (t, 3H,
OCH2CH3, J=7.1 Hz), 1.4 (m, 4H, CH2(CH2)2CH3),
1.8 and 2.1 (2m, 2H, CH2(CH2)2CH3), 4.15 (m, 2H,
H-5 and H-5%), 4.35 (q, 2H, OCH2CH3, J=7.1 Hz),
5.8 (m, 1H, H-2). 13C NMR: l 14.02, 14.23, 22.46,
28.56, 38.22, 42.51, 62.62, 84.53, 161.82, 162.10. GC–
MS: 215 (M+, 5), 182 (100), 171 (31.9), 168 (32.8), 158
(14.2), 142 (24.9), 112 (87.2), 108 (14.1), 101 (15.4),
100 (15.8), 86 (31), 59 (14.2), 54 (14.7), 45 (16.8), 41
(31.4). HRMS calcd for C10H17O2NS: 215.1054.
Observed: 215.0980.
1
4.3.5. Methyl 2-butyl-3-thiazoline-4-carboxylate 2e. H
NMR: l 0.9 (t, 3H, (CH2)3CH3, J=7 Hz), 1.4 (m,
4H, CH2(CH2)2CH3), 1.8 and 2.1 (2m, 2H,
CH2(CH2)2CH3), 3.9 (s, 3H, OCH3), 4.15 (m, 2H, H-
5), 5.8 (m, 1H, H-2). 13C NMR: l 13.86, 22.31, 28.37,
38.06, 42.34, 53.11, 84.32, 161.66, 162.08. GC–MS:
201 (M+, 11), 168 (100), 154 (35.3), 144 (18.1), 142
(16.5), 127 (14.8), 113 (25.3), 112 (80.8), 108 (15.9), 59
4.3.11. Isopropyl 2-ethyl-3-thiazoline-4-carboxylate 2k.
1H NMR: l 1 (t, 3H, CH2CH3, J=7.3 Hz), 1.35 (d,

1286
X. Fernandez, E. Dun˜ach / Tetrahedron: Asymmetry 12 (2001) 1279–1286
6H, OCH(CH3)2, J=6.3 Hz), 1.8 and 2.1 (2m, 2H,
CH2CH3), 4.2 (dd, 2H, H-5), 5.2 (octuplet, 1H,
OCH(CH3)2, J=6.3 Hz), 5.8 (1H, m, H-2). 13C NMR:
l 10.51, 21.78, 31.42, 42.60, 70.61, 85.82, 161.34,
162.56. GC–MS: 201 (M+, 28.3), 172 (20.1), 172 (20.1),
159 (22.4), 130 (100), 126 (10.9), 114 (27.1), 113 (19.2),
112 (75.2), 87 (19.2), 86 (31.5), 59 (13), 45 (18.9), 43
(56.6).
References
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(m, 1H, CH(CH3)2), 4.1 (m, 2H, H-5), 5.2 (octuplet,
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4.4. Synthesis of ethyl 2-methyl-2-thiazoline-(4R)-
carboxylate 4b
A mixture of L-cysteine ethyl ester hydrochloride (1.85
g, 0.01 mol), ethyl acetimidate hydrochloride20 (1.72 g,
0.01 mol) and dry triethylamine (1.01 g, 0.1 mol) in
CH2Cl2 (20 mL) was stirred overnight at room temper-
ature. CH2Cl2 was removed in vacuo and saturated
aqueous NaCl (20 mL) was added and the solution was
extracted three times with dry diethyl ether (3×20 mL).
The organic phase was dried over MgSO4 and the
solvent evaporated to afford the title compound as a
colorless oil (1.7 g, 98%). 1H NMR: l 1.3 (t, 3H,
OCH2CH3, J=7.2 Hz), 2.3 (d, 3H, CH3,=1.7 Hz), 3.6
(m, 2H, H-5 and H-5%), 4.3 (qd, 2H, OCH2CH3, J=1.3
and 7.2 Hz), 5.1 (tq, 1H, H-4, 1.7 and 9.4 Hz). 13C
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170.94. GC–MS: 173 (M+, 0.3), 100 (100), 86 (11), 59
(41.3), 58 (9.6), 42 (7.5).
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Acknowledgements
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We thank the cooperation with Dr. R. Faure, Faculte´
des Sciences de St Jeroˆme, Marseille, France, for his
contribution in recording 2D NMR spectra. We also
thank the French Ministry of Education for a doctoral
scholarship to X.F.
20. Dow, A. Org. Synth., Coll. I 1941, 5–6.
.