The synthesis, N-alkylation and epimerisation study of a phthaloyl derived?thiazolidine

Article abstract of DOI:10.1016/j.tet.2008.04.097

The synthesis of the phthaloyl protected thiazolidine, N-phthaloyl-methyl-2(R)-thiazolidine-4(R)-methyl ester, 2, and a study of its susceptibility to epimerise in a range of solvents, using ¹H NMR spectroscopy, are described. Compound 2 was further reacted to yield the thiazole amino acid derivative, 3, and an N-alkylated thiazolidine derivative, 6, as a single diastereoisomer. The N-alkylation of 2, using mild bases, resulted in the formation of a mixture of diastereoisomers of 2 (2R,4R) and (2S,4R). Successful cleavage of the methyl ester and the phthaloyl protecting groups was achieved, giving rise to the formation of the two heterocyclic building blocks, 4 and 5.

Full text of DOI:10.1016/j.tet.2008.04.097

Tetrahedron 64 (2008) 6794–6800
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The synthesis, N-alkylation and epimerisation study of a phthaloyl
derived thiazolidine
*
*
Emma B. Veale , John E. O’Brien, Thomas McCabe, Thorfinnur Gunnlaugsson
School of Chemistry, Center for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the phthaloyl protected thiazolidine, N-phthaloyl-methyl-2(R)-thiazolidine-4(R)-methyl
ester, 2, and a study of its susceptibility to epimerise in a range of solvents, using 1H NMR spectroscopy,
are described. Compound 2 was further reacted to yield the thiazole amino acid derivative, 3, and an N-
alkylated thiazolidine derivative, 6, as a single diastereoisomer. The N-alkylation of 2, using mild bases,
resulted in the formation of a mixture of diastereoisomers of 2 (2R,4R) and (2S,4R). Successful cleavage of
the methyl ester and the phthaloyl protecting groups was achieved, giving rise to the formation of the
two heterocyclic building blocks, 4 and 5.
Received 11 February 2008
Received in revised form 9 April 2008
Accepted 24 April 2008
Available online 30 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
derivative 3. We also carried out the N-alkylation of the thiazolidine
ring with the aim of forming other novel functionalised thiazole
The heterocycles oxazole and thiazole are found in many
naturally based peptides and peptolides isolated from marine
organisms such as fungi, algae, etc. Many of these natural products
have been found to be cytotoxic substances and consequently
are potential therapeutic agents.1 Their activities, including cyto-
toxcity, multiple drug resistance, as well as their metal binding and
transport properties, have been investigated in detail.2 Because of
this, there currently exists a significant interest in the syntheses of
such products and their analogues.2 For instance, the total synthesis
of lyngbyabellin A, isolated from the marine cyanobacterium
Lyngbya majuscula, has been achieved by Yokokawa et al.,3 where
several functionalized thiazole carboxylic acids were synthesised
via the oxidation of the corresponding thiazolidines. The thiazoli-
dine ring is of significant medicinal importance, being found in
many biological structures such as penicillin4 while its formation,
form the amino acid cysteine, also occurs in many important bi-
ological processes.5 However, thiazolidine based carboxylic acids
are known to epimerise in solution6 an issue, which is of significant
importance for the use of such structures in potential therapeutic
reagents. Aspartofanongoinganticancerdrugdiscoveryprogramme
in our laboratory, we were interested in synthesising and in-
corporating thiazole containing amino acid derivatives into well-
known DNA binding compounds. Our synthetic strategy involved the
preparation of the orthogonally N-protected phthaloyl-based thia-
zolidineaminoacid2, whichuponoxidationgavethedesiredthiazole
based amino acids, which could then be incorporated into many of
the DNA binding motifs developed within our laboratory. This paper
describes the synthesisand the characterisation of these compounds,
as well as the epimerisation studies carried out on compound 2 using
1H NMR and X-ray crystallography diffraction analysis.
2. Results and discussion
2.1. Synthesis
The synthesis of the phthaloyl derived thiazolidine 2 and the
three thiazole containing heterocyclic building blocks 3–5 is shown
in Scheme 1. A number of methods for the synthesis of amino acid-
derived thiazoles are known and include: (i) condensation of an
amino acid-derived thioamide with ethyl bromopyruvate (a mod-
ification of the Hantzsch reaction);7 (ii) condensation of enantio-
pure N-protected
esters;8 (iii) condensation between cysteine esters and N-protected
imino esters;2a,b and (iv) cyclodehydration of
-hydroxythioamides
a-amino aldehydes or glyoxals with L-cysteine
b
using Burgess reagent.9 Thiazolidines synthesised by the last three
procedures are readily converted into thiazoles by oxidation.
In our endeavour, the second reaction method shown above was
chosen for the preparation of the thiazole derivative 3, Scheme 1.
The phthaloyl protecting group was utilised as it is stable to both
acid and base and can usually be cleaved by reaction with hydrazine
in ethanol.10 Moreover, we have in the past used related diimides
quite successfully in our development of anticancer agents, and
it has not been used previously in the synthesis of targets such as
5. Hence, the synthesis of 5 involved the initial hydrolysis of
* Corresponding authors.
E-mail addresses: vealeem@tcd.ie (E.B. Veale), gunnlaut@tcd.ie (T.
Gunnlaugsson).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.097

E.B. Veale et al. / Tetrahedron 64 (2008) 6794–6800
6795
O
O
SH
O
O
N
(a)
S
N
+
HCl.H2N
O
O
O
O
O
1
O
(b)
O
H
S
N
(c)
(e)
N
N
H
N
O
O
S
O
O
3
2
O
O
(d)
O
S
H2N
N
N
N
O
O
O
4
5
O
HO
Scheme 1. Synthesis of thiazolidine 2 and thiazoles 4 and 5. (a) TFA, CHCl3, rt; (b)
KHCO3, EtOH/H2O, rt; (c) MnO2, pyridine, CH2Cl2, reflux; (d) HCl, acetone/H2O (7:1),
reflux; (e) H2NNH2 (2 equiv), EtOH, rt.
phthalimidoacetaldehyde diethyl acetal using a mixture of TFA and
chloroform, which gave 1 in quantitative yield as a white solid
without the need for further purification. The cyclocondensation
Figure 2. Crystal structure of 2, hydrogen atoms are shown in green.
reaction betweentheHClsaltof L-cysteine methyl esterand1, at rt for
further purification. Carrying out this reaction in the absence of
pyridine did not give 3 in high purity. Compound 3 was charac-
terised using conventional methods. Additionally, crystals were
grown of 3 by slow evaporation from a 3:1 mixture of MeOH and
CH2Cl2 that were suitable for X-ray crystallography diffraction
analysis. The resulting crystal structure is shown in Figure 3,
showing the fully oxidised ring system.
5 h, gave the thiazolidine 2 in 79% yield, after a recrystallisation from
methanol. The 1H NMR (CDCl3, 600 MHz) spectrum of 2 is shown in
Figure 1 and shows that the compound was obtained as a single dia-
stereoisomer. Analysis of the spectrum showed that the Ha and Ha0
protons are diastereotopic appearing as two dd at 4.15 and 4.05 ppm,
respectively, with a coupling constant of 14.5 Hz. They are also cou-
pled to Hz, which appears as a dd at 4.86 ppm. The second geminal
pair Hb and Hb0 appeared as a dd and a t at 3.33 and 2.92 ppm, re-
spectively. Each proton is coupled to each other as well as Hx, which
shows as a triplet at 3.82 ppm. The NH proton appears as a broad
singlet at 2.61 ppm while the protons of the methyl ester appear as
a sharp singlet at 3.80 ppm. Similar NMR studies were also performed
using DMSO-d6. The resulting spectrum showed that the NH proton
appeared as a triplet at 3.39 ppm (located using 15N HSQC NMR),
because of its coupling to both adjacent chiral protons, Hx and Hz.
Single off-white crystals of 2 were grown by the slow evapo-
ration of CH2Cl2 overnight from a suspension of the compound in
MeOH. They were suitable for X-ray diffraction analysis. The
resulting crystal structure is shown in Figure 2 (see Section 4 for
further details11) showing that the phthaloyl group is faced over top
of the thiazolidine ring. The unit cell showed only the presence of
a single molecule, and hence a single diastereoisomer was ob-
served. This compliments the results observed in the solution
studies. Assuming that the reaction was stereospecific at the C-2
position, the stereochemistry of 2 was assigned as (2R,4R).
The removal of the orthogonal protecting groups was achieved
to give 4 and 5, respectively. Cleavage of the methyl ester group was
achieved by an acid-catalysed hydrolysis using HCl in a 7:1 mixture
of acetone and H2O. This gave 4 as fine colourless needles in 55%
yield, without the need for further purification.12 For the cleavage
of the phthaloyl protecting group a number of hydrazinolysis re-
actions were attempted. When the deprotection was carried out at
reflux temperature using small excess of H2NNH2$H2O, the thiazole
ring decomposed. This resulted in the formation of 5, which was,
however, difficult to separate from the phthaloylhydrazide
byproduct and unreacted 3, using column chromatography on flash
silica. The hydrazinolysis was, however, achieved by the slow ad-
dition of 2 equiv H2NNH2 to a boiling suspension of 3 in EtOH,
followed by stirring the resulting clear mixture at rt for 4 h, after
which the phthaloylhydrazide was removed by suction filtration.
This gave the thiazole 5 in 53% yield following an acid–base ex-
traction of the filtrate. The 1H NMR (CDCl3, 400 MHz) spectrum
showed that 5 was formed in high purity and the successful for-
mation of 5 was also further confirmed by X-ray crystallography
diffraction analysis, Figure 4, from crystals grown by slow evapo-
ration of CH2Cl2 from a saturated solution of 5 in MeOH.
The orthogonally protected thiazole 3 was formed by oxidising 2
using activated MnO2 for 5 days in the presence of pyridine in dry
CH2Cl2 at reflux temperature, in 63% yield without the need for
z
O
a,a'
O
H
S
2
4
N
b,b'
O
N
H
OCH3
3
Hx
H3, H4
H2, H5
H
O
x
5
Hb, Hb’
Ha, Ha’
Hz
NH
8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4
(ppm)
Figure 1. 1H NMR (CDCl3, 600 MHz) spectrum of 2.
Figure 3. Crystal structure of 3.

6796
E.B. Veale et al. / Tetrahedron 64 (2008) 6794–6800
for X-ray crystallography diffraction analysis. The crystal structure
of 2a is shown in Figure 6, from which the absolute stereochemistry
was indeed assigned as (2S,4R), confirming that the epimerisation
of 2 must have occurred at the C-2 position of the thiazolidine ring.
The possible mechanism for this base-catalysed epimerisation
is shown in Scheme 3, which would involve the deprotonation of
the acidic NH proton causing the thiazolidine ring to open, and
the formation of a Schiff base intermediate. This system then
undergoes a ring closure, which gives rise to changing stereo-
chemistry of the C-2 chiral centre,6d,e which further supports the
suggested mechanism shown in Scheme 3. While such mechanism
has been proposed by strong bases before, then, to the best of our
knowledge, the deprotonation by a weak base such as NEt3 has not
been reported within the literature.
Figure 4. Crystal structure of 5.
Other attempts to alkylate 2 using bases such as K2CO3 (1 equiv)
in CH3CN, only lead to the formation of a 50:50 mixture of 2 and 2a.
However, by carrying out the reaction in the presence of KI and
increasing the relevant concentration of K2CO3 and benzylchloride
to 1.5 and 1.2 equiv, respectively, seem to overcome this epimeri-
zation. Hence, compound 6 (ESMS analysis gave m/z¼419 for
[MþNa]) was obtained as an off-white solid in 69% yield, following
purification by column chromatography on neutral flash silica
(ethyl acetate/hexane 98:2/50:50 and 1% NEt3). According to 1H
NMR (CDCl3, 400 MHz) analysis of 6, it was also formed as a single
diastereoisomer, Figure 7. However, we were unable to determine
the absolute stereochemistry of this new product. Compound 6 was
2.2. N-Alkylation of the thiazolidine 2
For the N-alkylation of thiazolidine 2, Scheme 2, a number of
reactions were carried out by varying the nature of the base and the
reaction conditions. These are summarised in Table 1. The two first
attempts involved the use of NEt3 as a base and benzylchloride as
the alkylating agent in either CH2Cl2 or CH3CN, respectively.
However, 1H NMR analysis of the resulting products demonstrated
that both reactions had been unsuccessful in giving the desired
alkylated product. Instead, both spectra showed the presence of
a mixture of diastereoisomers of 2.
further characterised by other conventional methods. Here, the 13
C
NMR (CDCl3, 400 MHz) showed the presence of the three methy-
lene carbons at 61.8, 42.8 and 33.4 ppm, respectively, while the
seven resonances for the aromatic rings appeared between 137.8
and 122.6 ppm.
O
O
H
H
S
S
RX, Base
N
N
The alkylation reaction was also carried out by using CH3I. This
again, gave rise to the formation of a 55:45 mixture of the suc-
cessfully alkylated (2R,4R) diastereoisomer 7 and the (2S,4R) dia-
stereoisomer 2a. The successful formation of 7 was confirmed by
1H NMR analysis as well as by ESMS analysis, which gave m/z¼434
and 329 for [MþNa]þ of 7 and 2a, respectively. Instead of separating
these products, the mixture was oxidised by employing activated
MnO2, which resulted in the cleavage of the N-methyl group and in
the formation of 3 according to the 1H and 13C NMR (CDCl3,
400 MHz).
N
N
R
H
O
2
O
O
O
O
O
6: R = CH2C6H5
7: R = CH3
Scheme 2. Synthesis of 6 and 7 (see Table 1) from 2.
By comparing these spectra with that observed for 2 (Fig. 1) the
ratio of these two diastereoisomers were approximately 50:50,
Figure 5. From the 1H NMR we were able to assign the absolute
stereochemistry of one of these diastereoisomers as (2R,4R). As it
has been reported previously in the literature that thiazolidine
rings are susceptible to epimerisation, and that this process may
occur at the C-2 chiral centre of the thiazolidine ring,6 we specu-
lated that the stereochemistry of the other diastereoisomer might
be (2S,4R). In an attempt to verify this, the two products were
separated by column chromatography on flash silica using a mix-
ture of ethyl acetate, CH2Cl2 and hexane (3:2:3). This method of
purification was successful and the 1H NMR spectrum (CDCl3,
400 MHz) of the 50:50 mixture, 2 and 2a, is shown in Figure 5. As
means of determining the stereochemistry of 2a, an attempt was
made at growing crystals of the compound by the slow evaporation
from a solution mixture containing CH2Cl2 and MeOH. This resulted
in the formation of off-white single crystals, which were suitable
2.3. Epimerisation studies of 2
With the aim of further investigating the above epimerisation
process, we carried out detailed NMR studies on 2. As shown in
Figure 5, the apparent difference between the chemical shifts of the
C-2 protons of the (2R,4R) and the (2S,4R) diastereoisomers would
allow the process to be easily followed. The rate of epimerisation
was monitored by recording the 1H NMR spectra of 2 at 300 K
immediately after dissolving the compound in the appropriate
solvent until the process reached equilibrium. The solvents used in
these studies were CDCl3, (CD3)2SO, (CD3)2CO and C2D4O2. The
epimerisation of 2 was also followed using CDCl3 in the presence of
a small amount of (C2H5O)BF3, to determine if the process was also
acid-catalysed. Furthermore, as the crystals of 2 shown in Figure 6
were grown by the slow evaporation of CH2Cl2 from a saturated
solution of 2 in MeOH, we also monitored this process in (1:3)
mixture of CDCl3 and MeOD. The chemical shifts of the C-2, C-4 and
NH protons are shown in Table 2 for all of the systems investigated.
The stack plot of the 1H NMR spectra (CDCl3, 600 MHz) of 2 after
recording the sample over 5 days is shown in Figure 8. The change
in the resonance for the Hz proton at 4.87 ppm was followed. After
6 h, the signal for the Hz proton of the (2S,4R) diastereoisomer was
observed at 5.14 ppm. Upon integrating both signals, it was de-
termined that there was approximately a 4:1 ratio of the (2R,4R)/
Table 1
N-Alkylation of 2
Base
RX
Condition
Product
A
B
C
D
E
Et3N
Et3N
K2CO3
K2CO3
K2CO3
PhCH2Cl
PhCH2Cl
PhCH2Cl
PhCH2Cl
CH3Cl
D, 24 h
D, 21 h
D, 18 h
D, 18 h
D, 48 h
R¼H; R,R/S,S 95:5
R¼H; R,R/S,S 95:5
R¼H; R,R/S,S 50:50
R¼CH2Ph
R¼CH3; S,R 45%
R¼H; R,R 55%
Attempt A was carried out in CH2Cl2 while all other attempts were carried out in
CH3CN. Attempt D was carried out in the presence of KI.

E.B. Veale et al. / Tetrahedron 64 (2008) 6794–6800
6797
z
S
O
z
S
O
a,a'
H
a,a'
O
H
N
b,b'
N
b,b'
O
2
N
N
5
H
O
H
x
H
O
H
O
x
O
5.4
5.4
5.4
5.2
5.0
5.0
5.0
4.6
4.6
4.6
4.2
Ha,Ha’
4.0
4.0
3.8
3.8
3.8
3.6
3.6
3.6
3.4
3.4
3.4
3.2
3.0
3.0
3.0
2.8
2.8
2.8
2.6
2.6
2.6
4.8
4.8
4.8
4.4
Hb,Hb’
Hx
Hz
5.2
4.4
4.2
3.2
Ha,Ha’
Hb,Hb’
Hz
Hx
5.2
4.4
4.2
4.0
(ppm)
3.2
Figure 5. 1H NMR spectrum (CDCl3, 400 MHz) of (A) the 50:50 mixture of diastereoisomers (B) 2 and (C) 2a.
O
x
a,a'
H
S
2
N
b,b'
N
3
O
O
5
4
O
2'
Ha, Ha’
CH2
3'
5'
H2’–H6’
Hb, Hb’
4'
H2–H5
Hz
Hx
8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2
(ppm)
Figure 6. Crystal structure of 2a.
Figure 7. 1H NMR spectrum (CDCl3, 400 MHz) of 6.
(2S,4R) diastereoisomers present in solution. This process, while
being slow, reaches equilibrium after 5 days with a (2R,4R)/(2S,4R)
ratio of 1:2. When the above experiment was repeated in the
presence of a small amount of (C2H5O)BF3, the epimerisation of 2
also came to equilibrium after 5 days. However, unlike that seen
above, after 3 h there was 3:1 ratio of (2R,4R)/(2S,4R) and upon
reaching equilibrium there was a (2R,4R)/(2S,4R) ratio of 1:4 pres-
ent in solution. This would indicate that the process is also acid-
catalysed. Further evidence for this was given by the fact that the
epimerisation process in (CD3)2CO did not occur, even though the
polarities of CDCl3 and (CD3)2CO are quite similar. With this in
mind, the epimerisation of 2 was followed in C2D4O2 and was found
to reach equilibrium after 1.5 days with a (2R,4R)/(2S,4R) ratio of
1:1 and remained unchanged even after 4 days.
Table 2
Chemical shifts of the C-2, C-4 and NH protons of 2 and 2a, in a number of different
deuterated solvents
Solvent
CDCl3
C-2 (Hz)
C-4 (Hx)
NH
4.86 (2R,4R)
5.50 (2S,4R)
4.82 (2R,4R)
4.96 (2S,4R)
4.88 (2R,4R)
4.90 (2R,4R)
5.16 (2S,4R)
3.82 (2R,4R)
4.21 (2S,4R)
3.96 (2R,4R)
4.07 (2S,4R)
3.90 (2R,4R)
4.14 (2R,4R)
4.38 (2S,4R)
2.61 (2R,4R)
2.75 (2S,4R)
3.39 (2R,4R)
3.55 (2S,4R)
2.98 (2R,4R)
d
(CD3)2SO
(CD3)2CO
CD3CO2D
d
constant was determined to be 3ꢀ10ꢁ6 Sꢁ1. Strangely, it was found
that the epimerisation of 2 in all of the other solvents did not obey
first order or second order kinetics, and consequentlya rate constant
could not be determined. The final study undertaken involved fol-
lowing the epimerisation of 2 in a mixture of CDCl3 and MeOD (1:3).
When the spectrum was recorded in (CD3)2SO, the process came
to equilibrium after 6 days with a (2R,4R)/(2S,4R) ratio of 1:2. Typical
first order kinetics was observed for this process and the rate
H
O
O
O
H
H
N
H
S
S
S
N
N
N
2
2
N
N
5
5
O
O
O
H
H
O
O
O
S,R
R,R
O
O
O
2a
2
B-
Scheme 3. Possible mechanism for the C-2 epimerisation of 2 via a Schiff base intermediate to give 2a.

6798
E.B. Veale et al. / Tetrahedron 64 (2008) 6794–6800
z
S
O
z
S
O
H
H
N
N
2
2
+
N
N
4
4
H
O
H
O
Hz
H
O
O
H
O
O
Immediate
Hz
6 h
24 h
5 d
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
(ppm)
3.8
3.6
3.4
3.2
3.0
2.8
2.6
Figure 8. Stack plot of the 1H NMR spectra (CDCl3, 600 MHz) of 2.
After 12 h, formation of the (2S,4R) diastereoisomer was not ob-
served. Moreover, it was only after 8 days that the signal pertaining
to the Hz proton of the (2S,4R) diastereoisomer was observed and an
integration of each of the signals for the protons of the C-2 centre
gave a (2R,4R)/(2S,4R) ratio of 6:1. This indicated that the presence of
a protic solvent significantly reduces the rate of epimerisation,
perhaps through hydrogen bonding interactions with the NH of 2.
Deuterated solvents for NMR use were purchased from Apollo Ltd.
NMR spectra were recorded using a Bruker Avance III spectrometer,
operating at 400 MHz for 1H NMR and 100 MHz for 13C NMR and
a Bruker Avance II 600 MHz for 1H NMR and 150 MHz for 13C NMR.
Shifts are referenced relative to the internal solvent signals. NMR
data were processed using Bruker Win-NMR 5.0 software. Electro-
spray mass spectra were recorded on a Mass Lynx NT V 3.4 on
a Waters 600 controller connected to a 996 photodiode array de-
tector with HPLC-grade methanol, water or acetonitrile as carrier
solvents. Accurate molecular weights were determined by a peak-
matching method, using leucine enkephaline (H–Tyr-Gly-Gly-Phe-
Leu–OH) as the standard internal reference (m/z¼556.2771); all
accurate mass were calculated to ꢂ5 ppm. Melting points were
determined using an Electrothermal IA9000 digital melting point
apparatus. Infrared spectra were recorded on a Mattson Genesis II
FTIR spectrometer equipped with a Gateway 2000 4DX2-66 work-
station and on a Perkin Elmer Spectrum One FT-IR Spectrometer
equipped with Universal ATR sampling accessory. Solid samples
were dispersed in KBr and recorded as clear pressed discs or as neat
samples. Elemental analysis was carried out at the Microanalysis
Laboratory, School of Chemistry and Chemical Biology, University
College Dublin. X-ray diffraction studies were carried out by Dr. T.
McCabe, School of Chemistry, Trinity College Dublin, Dublin, Ireland.
3. Conclusion
In conclusion, the phthaloyl-based thiazolidine containing
amino acid 2 and the corresponding thiazole 3 were synthesised.
Deprotection of 3, whereby the methyl ester and the phthaloyl
protecting groups were removed to give the corresponding free
acid 4 and the free amine 5, respectively. Both deprotection steps
required efficient synthetic modification and the thiazole ring was
found to be sensitive to the conditions under which the hydrazi-
nolysis reaction was conducted.
Single crystals of 2, 2a and 3 were successfully grown by the
slow evaporation of CH2Cl2 from a saturated solution of the com-
pound in MeOH, while single crystals of 5 were obtained by
a crystallisation from EtOH. All were found to be suitable for X-ray
crystallography diffraction analysis. The crystal structures of 2 and
2a allowed for their absolute stereochemistry to be assigned as
(2R,4R) and (2S,4R), respectively, for these products.
4.2. N-[(Formyl)methyl]phthalimide (1)
A series of attempts were made at N-alkylating the thiazolidine
intermediate 2, and the synthesis was achieved by using K2CO3 as
a base in the presence of KI. This gave the alkylated product, 6, as
a single diastereoisomer. All other attempts resulted in the for-
mation of a mixture of the (2R,4R) and the (2S,4R) diastereoisomers
of 2. The rate of epimerisation of 2 was monitored in a range of
solvents by 1H NMR. It was found that the rate of epimerisation
increased in the presence of acid whereas it decreased in polar
Compound 1 was prepared by stirring phthalimido-acetaldehy-
dediethylacetal (26.0 g, 98 mmol) in a mixture of TFA (175 mL) and
CHCl3 (350 mL) in an ice/water bath, under an argon atmosphere,
for 1 h. The reaction mixture was stirred at rt for a further 5 h. The
solvent was removed in vacuo and co-evaporated with CH2Cl2
several times, to remove the remaining traces of TFA. This yielded
the product as an off-white solid (18.78 g,100%). No purificationwas
necessary. m.p. 102–103 ꢃC. Found: C, 63.23; H, 3.02; N, 6.58%.
solvents. From these results we can conclude that when L-cysteine
methyl ester is reacted with a phthaloyl protected aldehyde a single
diastereoisomer, as the kinetic product, is obtained in the solid
state. However, over time, selective inversion occurs to give a mix-
ture of C-2 epimeric thiazolidines.
C10H7NO3 requires C, 63.49; H, 3.73; N, 7.40%; dH (400 MHz, CDCl3)
9.67 (1H, s, CHO), 7.90 and 7.78 (4H, AA0BB0 system, Phth), 4.58 (2H,
s, CH2); dc (100 MHz, CDCl3) 193.2 (CH), 167.1, 133.9, 131.4, 123.2,
46.9; m/z: 190 (MþH)þ; nmax (KBr)/cmꢁ1 3100, 2965, 2850, 1580.
4. Experimental
4.1. General
4.3. N-Phthaloyl-methyl-2(R)-thiazolidine-4(R)-methyl
ester (2)
Compound 2 was prepared by adding a solution of L-cysteine
All chemicals were obtained from Sigma–Aldrich, Fluka, or Lan-
caster and unless specified, were used without further purification.
methyl ester hydrochloride (32.47 g, 189.0 mmol, 2 equiv) in H2O
(250 mL) to the aldehyde 1 (18.0 g, 94.6 mmol, 1 equiv) suspended

E.B. Veale et al. / Tetrahedron 64 (2008) 6794–6800
6799
in EtOH (500 mL). KHCO3 (18.9 g, 189.0 mmol, 2 equiv) was then
added and the resulting mixture was stirred under argon at rt for
5 h with thiazolidine 2 gradually precipitating from the reaction
medium. The reaction was allowed to sit overnight at 0 ꢃC. The
crude product 2 (27.0 g, 93% yield) was collected by suction filtra-
tion and washed several times with EtOH. Recrystallisation from
solution was stirred at rt for 4 h. A white precipitate was produced
as the reaction progressed, indicating the formation of phthalhy-
drazide side-product. The reaction was allowed sit at rt overnight.
The voluminous white precipitated phthalhydrazide (6.24 g, 97%
yield) was collected by suction filtration and washed with a little
EtOH (1H, 13C NMR and MS confirmed the structure to be C8H6O2).
The filtrate and washings were evaporated under reduced pressure.
The white residue was redissolved in EtOH and any remaining
precipitate was collected by suction filtration and washed with
a little EtOH. The filtrate and washings were evaporated under
reduced pressure. This procedure was repeated until an oil-like
residue was obtained. The residue was then dissolved in H2O and
extracted three times with CHCl2. The combined chloroform layers
were washed three times with HCl (0.1 M) and the combined
aqueous phases were extracted two times with CH2Cl2. The aque-
ous phase was brought to pH 12 by adding NaOH (0.1 M) and
extracted three times with CHCl2. The solvent was removed in
vacuo to give 5 as an off-white solid (3.6 g, 53% yield). m.p. 162–
163 ꢃC; HRMS: 195.0125 ([MþNa]þ. C6H8N2O2NaS requires
195.0229); dH (400 MHz, CDCl3) 8.13 (1H, s, CH), 4.22 (2H, s, CH2),
3.94 (3H, s, OCH3); dc (100 MHz, CDCl3) 175.4 (CO), 161.5 (C), 146.3
(C), 128.3 (CH), 51.9 (CH3), 43.52 (CH2); m/z: 195 (MþNa)þ; nmax
(KBr)/cmꢁ1 2957, 2843, 2810, 1650.
MeOH yielded 2 as a white crystalline fibrous solid (22.7 g, 79%).
23
m.p. 81–82 ꢃC; [
a
]
ꢁ39.4 (c¼5.3 mgcgꢁ3, CHCl3). Found: C, 54.08;
D
H, 4.23; N, 8.79%. C14H14N2O4S requires C, 54.89; H, 4.61; N, 9.14%;
HRMS: 329.0562 ([MþNa]þ C14H14N2O4NaS requires 329.0572); dH
(400 MHz, CDCl3) 7.87 and 7.74 (4H, AA0BB0 system, Phth), 4.86 (1H,
dd, J¼8.5 and 4.0 Hz, Hz), 4.14 (1H, dd, J¼14.5, 4.0 Hz, Ha), 4.06 (1H,
dd, J¼14.0, 8.5 Hz, Ha0), 3.82 (1H, dd, J¼9.5, 7.6 Hz, Hx), 3.80 (3H, s,
OCH3), 3.33 (1H, dd, J¼14.0, 6.5 Hz, Hb), 2.92 (1H, dd, J¼10.0, 8.0 Hz,
Hb0), 2.53 (1H, br s, NH); dc (100 MHz, CDCl3) 170.9 (CO), 168.1 (CO),
134.1 (CH), 131.7 (CH), 123.5 (CH), 68.2 (CH), 65.5 (CH), 52.5 (CH3),
41.1 (CH2), 38.2 (CH2); m/z: 329 (MþNa)þ; nmax (KBr)/cmꢁ1 3500,
3180, 2901, 2850, 1603.
4.4. N-Phthaloyl-methyl-thiazole-4-methyl ester (3)
Compound 3 was prepared by stirring 2 (22.50 g, 73.9 mmol,
1 equiv), activated MnO2 (224.9 g, 2580 mmol, 35 equiv) and pyri-
dine (6.60 g, 6.7 mL, 83.5 mmol, 1.13 equiv) at reflux in dry CH2Cl2
under an argon atmosphere for 5 days. The reaction mixture was
filtered hot through celite, washing several times with CH2Cl2. The
filtrate and washings were evaporated to dryness and the white
residue was redissolved in CH2Cl2 and washed three times with HCl
(0.1 M) and once with H2O. The organic layer was dried over
MgSO4, filtered and evaporated to dryness to give the product as
a white solid (13.39 g, 63% yield) after recrystallisation from MeOH.
m.p. 164–164 ꢃC. Found: C, 54.99; H, 2.76; N, 8.68%. C14H10N2O4S
requires C, 55.62; H, 3.33; N, 9.27%; HRMS: 325.0265 ([MþNa]þ
C14H10N2O4NaS requires 325.0259); dH (400 MHz, CDCl3) 8.15 (1H,
s, CH), 7.93 and 7.77 (4H, AA0BB0 system, Phth), 5.25 (2H, s, CH2),
3.95 (3H, s, OCH3); dc (100 MHz, CDCl3) 166.7 (C]O), 165.6 (C]O),
161.1 (C), 146.3 (C), 134.4 (CH), 131.3 (C), 128.3 (CH), 123.7 (CH), 52.0
(CH3), 38.7 (CH2); m/z: 325 (MþNa)þ; nmax (KBr)/cmꢁ1 3260, 3150,
2701, 2650, 1589.
4.7. N-Phthaloyl-methyl-3-benzyl-2(R)-thiazolidine-4(R)-
carboxylate (6)
Compound 6 was prepared by treating 2 (0.15 g, 0.49 mmol,
1 equiv) with K2CO3 (0.102 g, 0.74 mmol, 1.5 equiv) in dry acetoni-
trile at 40 ꢃC for 1 h. Benzylchloride (0.067 ml, 0.59 mmol,1.2 equiv)
and KI (0.098 g, 0.59 mmol, 1.2 equiv) were then added and the re-
action mixture was stirred at 80 ꢃC for 3 days. The solvent was then
removed in vacuo and the residue was dissolved in CH2Cl2 and
washed twice with water. The organic layer was dried over MgSO4,
filtered and evaporated to dryness to give the product (0.13 g, 69%)
as a light yellow solid following purification by column chroma-
tography on neutral flash silica (ethyl acetate/hexane 98:2/50:50
and 1% NEt3). m.p. 94–96 ꢃC; HRMS: 419.1023 ([MþNa]þ
C21H20N2O4NaS requires 419.1041); dH (400 MHz, CDCl3) 7.72 and
7.68 (4H, AA0BB0 system, Phth), 7.19 (2H, brs, H20, H60), 7.02–6.97 (3H,
m, H30, H40, H50), 4.67 (1H, dd, J¼8.5, 6.0 Hz, Hz), 3.82 (1H, t, J¼7.5 Hz,
Hx), 3.85 (3H, s, OCH3), 3.83 (1H, dd, J¼14.0, 4.5 Hz, Ha), 3.75 (1H, dd,
J¼14.0, 8.0 Hz, Ha0), 3.60 (1H, dd, J¼14.0, 6.0 Hz, Hb), 2.92 (1H, dd,
J¼12.0, 7.5 Hz, Hb0); dc (100 MHz, CDCl3) 171.9 (CO),167.2 (CO),137.8
(C), 133.2 (CH), 131.6 (C), 128.6 (CH), 127.7 (CH), 126.8 (CH), 122.6
(CH), 71.6 (CH), 70.6 (CH), 61.8 (CH2), 52.1 (CH3), 42.8 (CH2), 33.4
(CH2); m/z: 419 (MþNa)þ; nmax (KBr)/cmꢁ1 3500, 3180, 2901, 2850,
1603.
4.5. N-Phthaloyl-methyl-thiazole-4-carboxylic acid (4)
Compound 4 was prepared by adding 2 (1.68 g, 5.5 mmol,
1 equiv) to a mixture of acetone (28 mL), H2O (17 mL) and con-
centrated HCl (8.5 mL). The suspension was stirred at reflux for
48 h. The reaction mixture was allowed to cool and any precipitate
present was collected by suction filtration and washed with a little
acetone. The filtrate and washings were evaporated under reduced
pressure. The residue was dissolved in K2CO3 (1.2 M). The solution
was filtered and brought to pH 1 by adding concentrated HCl. A
small amount of EtOH was added and the mixture was gradually
heated to dissolve the precipitate. On cooling the product separated
and was collected by suction filtration, washed with a little EtOH
and dried to yield 4 as fine colourless needles (0.87 g, 55%). m.p.
102–103 ꢃC; HRMS: 311.0114 ([MþNa]þ C13H8N2O4NaS requires
311.0102); dH (400 MHz, (CD3)2SO) 8.42 (1H, s, CH), 7.95 and 7.90
(4H, AA0BB0 system, Phth), 5.12 (2H, s, CH2); dc (100 MHz, CDCl3)
16.1 (C]O), 165.3 (C]O), 161.3 (C), 146.6 (C), 134.8 (CH), 131.4 (C),
12.6 (CH), 123.5 (CH), 39.2 (CH2); m/z: 311 (MþNa)þ; nmax (KBr)/
cmꢁ1 3260, 3150, 2650, 1589, 1360.
4.8. Crystal data (2)
C
14H14N2O4S, M¼306.33, monoclinic, a¼9.673(3), b¼5.2263(13),
c¼14.1444(4) Å,
a
¼90ꢃ,
b
¼109.251(4)ꢃ,
g
¼90ꢃ, U¼675.1(3) Å3,
T¼123 K, space group P2(1), Z¼2,
m
(Mo K
a
)¼0.26 mmꢁ1, 4434 re-
flections collected, 1944 unique, (Rint¼0.0241), R¼0.0274,
wR2[I>2
677805.
s
(I)]¼0.0787, Flack¼0.11(13). CCDC deposition number:
4.9. Crystal data (2a)
28H28N4O8S2,
M¼612.66,
C
monoclinic,
a¼13.6914(11),
4.6. 2-Aminomethyl-thiazole-4-carboxylate (5)
b¼8.6680(7), c¼23.5487(18) Å,
a
¼90ꢃ,
b
¼90.4720(10)ꢃ,
g
¼90ꢃ,
U¼2789.2(4) Å3,T¼123 K, space group C2, Z¼4,
m(MoK
a
)¼0.25 mmꢁ1
,
Compound 5 was prepared by adding hydrazine monohydrate
(3.9 g, 3.8 mL, 79.4 mmol, 2 equiv) to a suspension of 2 (12 g,
39.7 mmol, 1 equiv) in boiling EtOH (180 mL). The resulting
6585 reflections collected, 6384 unique, (Rint¼0.0178), R¼0.0328,
wR2[I>2
677802.
s(I)]¼0.0876, Flack¼0.03(4). CCDC deposition number:

6800
E.B. Veale et al. / Tetrahedron 64 (2008) 6794–6800
J. S.; Jolliffe, K. A.; Pattenden, G.; Skae, M. Tetrahedron 2003, 59, 6979–6990;
4.10. Crystal data (3)
(i) Moody, C. J.; Bagley, M. C. J. Chem. Soc., PerkinTrans.11998, 601–607; (j) Xia, Z.;
Smith, C. D. J. Org. Chem. 2001, 66, 3459–3466.
3. Yokokawa, F.; Sameshima, H.; Shioiri, T. Tetrahedron Lett. 2001, 42,
4171–4174.
4. (a) Sheehan, J. C.; Henery-Logan, K. R. J. Am. Chem. Soc. 1957, 79, 1262–1263; (b)
Sheehan, J. C.; Henery-Logan, K. R. J. Am. Chem. Soc. 1959, 81, 3089–3094.
5. (a) Kallen, R. G. J. Am. Chem. Soc. 1971, 93, 6236–6248; (b) Abbott, E. H.; Martell,
A. E. J. Am. Chem. Soc. 1970, 92, 1754–1759; (c) Yang, I. Y.; Khomutov, R. M.;
Metzler, D. E. Biochemistry 1974, 13, 3877–3884; (d) Rinaldi, A.; DeMarco, C.
Arch. Biochem. Biophys. 1970, 138, 697–699; (e) Buell, M. V.; Hansen, R. E. J. Am.
Chem. Soc. 1960, 82, 6042–6049; (f) Nagasawa, H. T.; Goon, D. J. W.; de Master,
E. B. J. Med. Chem. 1978, 21, 1274–1279; (g) Nagasawa, R. E.; Goon, D. J. W.; Zera,
R. T.; Yuzon, D. L. J. Med. Chem. 1984, 27, 591–596.
C
14H10N2O4S, M¼302.3, triclinic, a¼5.8552(13), b¼7.8771(17),
c¼14.112(3) Å,
a
¼84.814(4)ꢃ,
b
¼89.300(4)ꢃ,
g
¼82.239(4)ꢃ, U¼
642.3(2) Å3, T¼123 K, space group P-1, Z¼2,
m
(Mo K
a
)¼0.27 mmꢁ1
,
6399 reflections collected, 3095 unique, (Rint¼0.0191), R¼0.0365,
wR2[I>2
s
(I)]¼0.0994. CCDC deposition number: 677804.
4.11. Crystal data (5)
C6H8N2O2S, M¼172.20, monoclinic, a¼5.8172(98), b¼13.3627(19),
6. (a) Pesek, J. J.; Frost, J. H. Tetrahedron 1975, 31, 907–913; (b) Refouvelet, B.;
Robert, J.-F.; Couquelet, J.; Tronche, P. J. Heterocycl. Chem. 1994, 31, 77–80; (c)
Chiarino, D.; Ferrario, F.; Pellacini, F.; Sala, A. J. Heterocycl. Chem. 1989, 26, 589–
593; (d) Ponticelli, F.; Marinello, E.; Missale, M. C. Org. Magn. Reson. 1982, 20,
138–140; (e) Nagasawa, H. T.; Goon, D. J. W.; Shirota, F. N. J. Heterocycl. Chem.
1981, 18, 1047–1051; (f) Szilagyi, L.; Gyorgydeak, Z. J. Am. Chem. Soc. 1979, 101,
427–432.
c¼9.7714(14) Å,
a
¼90ꢃ,
b
¼97.06ꢃ,
g
¼90ꢃ, U¼753.81(18) Å3, T¼123 K,
space group P2(1)/n, Z¼4,
m
(Mo K
a
)¼0.38 mmꢁ1, 7652 reflections
collected,
[I>2
1858
unique,
(Rint¼0.0217),
R¼0.0568,
wR2
s
(I)]¼0.1403. CCDC deposition number: 677803.
7. (a) Schmidt, U.; Utz, R. Angew. Chem., Int. Ed. Engl. 1984, 23, 725–726; (b)
Schmidt, U.; Gleich, P. Angew. Chem., Int. Ed. Engl. 1985, 24, 569–571; (c)
Schmidt, U.; Utz, A.; Lieberknecht, H.; Griesser, B.; Potzolli, B.; Bahr, J.; Wagner,
K.; Fischer, P. Synthesis 1987, 233–236.
8. (a) Hamada, Y.; Shibata, M.; Sugiuri, T.; kato, S.; Shioro, T. J. Org. Chem. 1987, 52,
1252–1255; (b) Groarke, M.; McKervey, M. A.; Moncrieff, H. M.; Nieuwenhuy-
zen, M. Tetrahedron Lett. 2000, 41, 1279–1282.
9. Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397–5400.
10. Curley, S. O. M.; McCormick, J. E.; McElhinney, S. R.; McMurry, B. T. H. ARKIVOC
2003, 7, 180–183.
Acknowledgements
We would like to thank Trinity College Dublin, the Research
Council for Science, Engineering and Technology (IRCSET) for
a postgraduate scholarship awarded to Dr. E.B.V. and Science
Foundation Ireland (SFI) for Frontier Research Programme (RFP)
Grant 2005.
11. The data were collected on a Bruker Smart Apex Diffractometer. Each crystal
was mounted on a 0.30 mm quartz fibre and immediately placed on the go-
niometer head in a 150 K N2 gas stream. The data sets were collected using
Smart Version 5.625 software run in multi-run mode and for each data set 2400
frames in total, at 0.3ꢃ per frame, were recorded. Data integration and reduction
was performed using Bruker Saintþ Version 6.45 software and corrected for
absorption and polarization effects using Sadabs Version 2.10 software. Space
group determinations, structure solutions and refinements were obtained using
Bruker Shelxtl Ver. 6.14 software. SMART Software Reference Manual, Version
5.625; Bruker Analytical X-Ray Systems: Madison, WI, 2001; Sheldrick, G. M.
SHELXTL, An Integrated System for Data Collection, Processing, Structure Solution
and Refinement; Bruker Analytical X-Ray Systems: Madison, WI, 2001.
12. Cross, D. F. W.; Kennerr, G. W.; Shepparda, R. C.; Stehr, C. E. J. Chem. Soc. 1963,
2143–2150.
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