Memory of chirality in the electrochemical oxidation of thiazolidine-4-carboxylic acid derivatives

Article abstract of DOI:10.3987/COM-09-S(S)101

Memory of chirality in the electrochemical oxidation of thiazolidine-4-carboxylic acid derivatives was observed. The relatively larger size of sulphur atom than the oxygen atom for oxazolidine-4-carboxylic acid derivative may slightly improved the enantioselectivities of the oxidized products. The bulkier penicillamine derivative 1c furnished 2c with much better enantioselectivity (91% ee) than that of the cysteine derivative 2b (85% ee). The presence of two extra dimethyl groups, for the penicillamine derivative improved the enantioselectivities of the thiazolidine derivatives from 85% ee to 91 % ee.

Full text of DOI:10.3987/COM-09-S(S)101

HETEROCYCLES, Vol. 80, No. 2, 2010
1177
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 1177 - 1185. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd August, 2009, Accepted, 13th October, 2009, Published online, 13th October, 2009
DOI: 10.3987/COM-09-S(S)101
MEMORY OF CHIRALITY IN THE ELECTROCHEMICAL OXIDATION
OF THIAZOLIDINE-4-CARBOXYLIC ACID DERIVATIVES†
George Ng’aNg’a Wanyoike, Yoshihiro Matsumura, Masami Kuriyama, and
Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14,
Bunkyo-machi, Nagasaki 852-8521, Japan. E-mail: onomura@nagasaki-u.ac.jp
†Dedicated to Professor Emeritus Akira Suzuki, Hokkaido University, on his 80th
birthday.
Abstract – Memory of chirality in the electrochemical oxidation of
thiazolidine-4-carboxylic acid derivatives was observed. The relatively larger size
of sulphur atom than the oxygen atom for oxazolidine-4-carboxylic acid
derivative may slightly improved the enantioselectivities of the oxidized products.
The bulkier penicillamine derivative 1c furnished 2c with much better
enantioselectivity (91% ee) than that of the cysteine derivative 2b (85% ee). The
presence of two extra dimethyl groups, for the penicillamine derivative improved
the enantioselectivities of the thiazolidine derivatives from 85% ee to 91% ee.
INTRODUCTION
The synthesis of optically active compounds on the basis of ‘memory of chirality’ continues to attract
much attention in asymmetric synthesis.1 In our previous studies on asymmetric synthesis via memory of
chirality, we reported that the non-Kolbe electrolysis2 of the oxazolidines afforded optically active
N,O-acetals with up to 80% ee (Scheme 1). 3 This highly enhanced enantiomeric excess was attributed to
the bulkiness of the ring system as well as the N-protecting group. We report herein that the non-Kolbe
O
O
Pt electrodes
Me
Me
Me
Me
2e
OMe
CO2H
N
N
NaOMe
in MeOH
30 oC
O
O
Ph
80% ee (74% yield)
Ph
Scheme 1. Electrochemical oxidation of oxazolidine derivative

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HETEROCYCLES, Vol. 80, No. 2, 2010
reaction of thiazolidine-4-carboxylic acid derivatives proceeds more efficiently than that of the
corresponding oxazolidines.
RESULTS AND DISCUSSION
Several thiazolidine compounds were synthesized and electrochemically oxidized in methanol. The
N-benzoylthiazolidine compound 1a, derived from cysteine afforded a racemic N,O-acetal 2a when
electrochemically oxidized using platinum electrodes in methanol at –30 οC. The use of graphite anode in
the electrochemical oxidation of 1a afforded 2a with 22% ee in 72% yield (Scheme 2). These
stereochemical results, albeit low, correlated well to those of the oxazolidine derivatives, 0% and 39% ee,
for the platinum and graphite anode, respectively.4
S
S
Me
Me
Me
Me
2e
*
CO2H
N
OMe
N
NaOMe
O
O
in MeOH
30 oC
2a
0% ee (70% yield)
22% ee (72% yield)
1a
Pt anode
graphite anode
Scheme 2. Electrochemical oxidation of thiazolidine derivative 1a
Electrochemical oxidation of a more bulky N-o-phenylbenzoylcysteine derivative 1b under the previously
optimized reaction conditions using platinum and graphite anode,3 furnished -methoxylated product 2b
with 85% ee and 80% ee for the platinum and graphite anode, respectively (Scheme 3). On the other hand,
use of graphite material as the cathode instead of platinum material did not affect the results.
S
S
Me
Me
Me
Me
2e
*
CO2H
OMe
N
N
30C
NaOMe
in MeOH
O
O
Ph
Ph
2b
1b
85% ee (58% yield )
80% ee (56% yield )
Pt anode
graphite anode
Scheme 3. Electrochemical oxidation of thiazolidine derivative 1b
This result shows that there was a slightly better enantioselectivity in the case of using platinum anode,
85% ee in the thiazolidine derivatives than that in the oxazolidine derivatives, 80% ee.
Treatment of 2b with acidic methanol at room temperature furnished almost racemic product, 1% ee after
stirring for 17 h (Scheme 4).

HETEROCYCLES, Vol. 80, No. 2, 2010
1179
cat. H2SO4
in MeOH
2b 85% ee
2b 1% ee
rt, 17 h
Scheme 4. Racemization of 2b under acidic condition
To improve the enantioselectivity, it was envisaged that the use of more bulky ring system could restrict
the rotation of the amide CO-N bond and thus promote the memory of chirality. On this basis, N-acyl
thiazolidine derived from optically active penicillamine was synthesized. Electrochemical oxidation of
the penicillamine derivative 1c in methanol at –30 οC, using 10 equiv of NaOMe with platinum electrodes
furnished N-acyl-N,O-acetal 2c with 91% ee in 54% yield (Scheme 5).
Me
Me
Me
Me
S
S
5
4
5
4
Me
Me
Me
Me
2e
*
OMe
CO2H
N
N
Pt anode
30C
O
O
NaOMe
Ph
Ph
91% ee
(54% yield)
in MeOH
1c
2c
Scheme 5. Electrochemical oxidation of penicillamine derivative 1c.
This was a great enhancement in the enantiomeric excess, from 85% ee in the cysteine derivative 2b to
91% ee in 2c. This improvement was ascribed to the presence of dimethyl groups at C5 in 1c. The
racemization of 2c in acidic methanol afforded 2c in 3% ee (Scheme 6).
cat. H2SO4
in MeOH
2c 91% ee
2c 3% ee
rt, 17 h
Scheme 6. Racemization of 2c under acidic condition
The bulkier compound may have had a greater restriction of rotation of the o-phenyl group prompting an
increased attack by the nucleophile, (MeO), from the less hindered side hence the larger enantiomeric
excess.
In order to compare the electrochemical result with the chemical method, 1c was oxidized using
ο
Pb(OAc)4 in methanol at –30 C. The chemical reaction proceeded slowly to afford 15% of
-methoxylated product 2c in 86% ee after 6 days (Scheme 7). The major isomer in the chemical
oxidation process had a similar configuration to that of electrochemical product as shown by the chiral

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HETEROCYCLES, Vol. 80, No. 2, 2010
HPLC analyses.
Pb(OAc)4
1c
2c
30C
86% ee
(15% yield)
NaOMe
in MeOH
Scheme 7. Chemical oxidation of 1c
Direct assignment of the absolute configuration for compounds 2b,c was not applicable, but the absolute
configuration could be inferred on the basis of the following reactions. In order to deduce the absolute
configuration of the methoxylated products and hence the plausible reaction mechanism for the
thiazolidine derivatives, 2,2,5R-trimethyl-3-o-phenylbenzonylthiazolidine-4R-carboxylic acid (1d) was
prepared from L-threonine (A)5 (Scheme 8).
Me
R
Me
Me
R
R
HS
HCl/Zn/MeOH
S
HO
CO2H
H2N
HCl
CO2H
CO2H
H2N
R
H2N
R
S
2
C
B
A
Me
Me
CO2H
S
S
o-PhBzCl
Me2CO
Reflux
Me
Me
Me
Me
CO2H
HCl
in pyridine
N
N
H
O
D
1d
Ph
Scheme 8. Preparation of cysteine derivative 1d
Electrochemical oxidation of 4R,5R-1d in methanol afforded -methoxylated compound 2d as a single
diastereomer (>99% de) (Scheme 9).
H
H
Me
H
CO2H
Me
H
OMe
S
2e
S
5
4
Me
Me
Me
Me
N
N
Pt anode
30C
O
O
NaOMe
Ph
Ph
>99% de
in MeOH
1d
2d
Scheme 9. Electrochemical oxidation of 1d
Cross peaks of the NOESY spectrum for 1d were observed between H-4 and 5-methyl, H-4 and
2a-methyl group, 2a-methyl group and 5-methyl, 2b-methyl group and H-5. With this result, the structure
of 1d was deduced as shown in Figure 1. In addition, NOESY analysis of 2d showed strong NOE

HETEROCYCLES, Vol. 80, No. 2, 2010
1181
between the methoxyl protons and H-5, H-4 and 5-methyl protons. These were the main diagnostic peaks
for the assignment of the configuration although other cross peaks were also observed as shown in Figure
1.
NOESY for 2d suggested that the methoxyl group and the 5-methyl had a trans-configuration and hence
-methoxylation process proceeded mainly by introduction of the nucleophile, (MeO), from the same
side (syn) as the carboxylate group to afford a retention product 4R,5R-2d predominantly. Thus, the
mechanism for the oxidative decarboxylation of the thiazolidine compounds is plausibly similar to that of
the oxazolidine derivatives,3 albeit the enantioselectivities for methoxylated products for the thiazolidines
were better (Scheme 10).
H
H
b
H3C
H3C
b
CH3
H
OCH3
CH3
H
COOH
S
2
S
2
5
4
5
H3C
4
H3C
N
N
a
a
O
O
Ph
4R,5R-2d
Ph
4R,5R-1d
Figure 1. NOESY for 1d and 2d
OMe
Me
N
S
MeO
Me
O
syn
CO2H
S
Me
N
Me
2b
4R-
92.5%
S
2e 2 F/mol
NaOMe
Me
N
O
Me
O
Pt cathode
Pt anode
MeOH, -30 ºC
Inversion
Me
N
S
1b
anti
Me
O
MeO
OMe
chiral iminium ion
2b
4S-
7.5%
Scheme 10. Reaction mechanism for electrochemical oxidation of 1b
CONCLUSION
In summary, the thiazolidine compound 1b afforded N,O-acetal 2b with better enantioselectivity than that

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HETEROCYCLES, Vol. 80, No. 2, 2010
of previously reported oxazolidine.3 The relatively larger size of sulphur atom than the oxygen atom may
be responsible for the difference in the enantioselectivities. The bulkier penicillamine derivative 1c
furnished 2c with much better enantioselectivity than that of the cysteine derivative 2b. Interestingly, both
the electrochemically obtained product and the chemical product had high enantiomeric excess, 91% ee
and 86% ee, respectively. It was, therefore deduced that the bulkiness of the ring as well as the
N-protecting group exclusively favored the formation of one stereoisomer by memory of chirality. The
methoxyl group was introduced through retention mechanism and this enantiomeric excess, 91% ee,
represents the highest ever-reported memory of chirality via carbenium ion intermediate.
EXPERIMENTAL
All commercial materials were used without further purification unless otherwise stated. Analytical thin
layer chromatography was performed on Merck silica gel 60 F254 plates (0.25mm). Compounds were
visualized by deeping in anisaldehyde followed by heating. Liquid chromatography was performed using
indicated solvent on silica gel 60 (200-300 mesh). IR spectra were obtained on a shimadzu FTIR-8100A.
1H NMR spectra were obtained on Varian Gemini 300, 400 and 500 MHz spectrometer and are reported
in parts per million () with tetramethylsilane (TMS) as the internal standard. The coupling constants are
recorded in hertz.
3-Benzoyl-2,2-dimethylthiazolidine-4R-carboxylic acid (1a)
L-cysteine hydrochloride monohydrate was converted into 2,2-dimethyl thiazolidine-4R-carboxylic acid
hydrochloride by condensation with acetone. The resultant compound was then treated with benzoyl
chloride in 200 mole equivalent of pyridine to afford 3-benzoyl-2,2-dimethylthiazolidine-4R-carboxylic
acid 1a (86% yield) as white needles.6 Mp 176-178 ˚C (uncorrected); []27.1 –162.1 (c 1.0, CHCl3), IR
D
1
(neat) 3200, 2980, 2930, 1748, 1595, 1400, 1220, 1180, 1130, 891, 700 cm1; H-NMR (300 MHz,
CDCl3)  7.50-7.30 (m, 5H), 4.83 (br s, 1H), 3.38-3.18 (m, 2H), 2.00 (s, 3H), 1.96 (s, 3H).
Electrochemical oxidation: Typical procedure
A solution of cysteine derivative 1a (132.5 mg, 0.5 mmol) and NaOMe (270 mg, 5 mmol) in MeOH (10
mL) was put into an undivided cell, stirred continuously and cooled to –30 °C. The cell was then
equipped with platinum plate electrodes (1 cm x 2 cm). Electrolysis of the solution with 2 F/mol at a
constant current (50 mA) afforded 3-benzoyl-4-methoxy-2,2-dimethylthiazolidine (2a) (79.1 mg, 63%
yield).7 HPLC analysis of 2a was carried out using Daicel Chiralpak AD (0.46 cm x 25 cm);
n-hexane:EtOH=15:1; wavelength, 210 nm; flow rate 0.5 mL/min; retention time, 18.3 min (minor), 23.7
min (major) 23% ee; 1H-NMR (300 MHz, CDCl3)  7.48-7.40 (m, 5H), 5.10 (d, 1H, J=3.6 Hz), 3.96 (dd,

HETEROCYCLES, Vol. 80, No. 2, 2010
1183
1H, J=0.9, 12.0 Hz), 3.19 (dd, 1H, J=3.60, 12.0 Hz), 3.00 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H); 13C-NMR
(100 MHz, CDCl3)  170.38 (1C), 138.05 (1C), 129.77 (1C), 128.31 (2C), 126.65 (2C), 94.02 (1C), 72.03
(1C), 54.62 (1C), 33.23 (1C), 29.51 (2C); IR (neat) 3050, 2977, 2932, 2828, 1651, 1464, 1362, 1230,
1196, 1071, 897, 793, 772, 906, 602 cm1. HR-MS[FAB(+)]: m/z calcd for C13H18NO2S [M+H]+
252.1058, found: 252.1070.
2,2-Dimethyl-3-o-phenylbenzoylthiazolidine-4R-carboxylic acid (1b)
This procedure is similar to that for the preparation of 1a. 2,2-Dimethyl thiazolidine-4R-carboxylic acid
hydrochloride (1.97 g, 10 mmol) was reacted with o-phenylbenzoyl chloride (2.16 g, 10 mmol) in 200
equivalent of pyridine to afford 3-o-phenylbenzoyl-2,2-dimethylthiazolidine-4R-carboxylic acid 1b (2.83
1
g, 83% yield). White solid, Mp 151-153 ˚C (uncorrected); []27.4 –195.7 (c 1.0, CHCl3); H-NMR (300
D
MHz, CDCl3)  7.57-7.28 (m, 9H), 4.26 (d, 1H, J=5.4 Hz), 2.87 (d, 1H, J=11.4 Hz), 2.20 (d, 1H, J=5.7
13
Hz), 1.95(s, 3H), 1.59 (s, 3H); C-NMR (100 MHz, CDCl3)  173.46 (1C), 169.47 (1C), 139.14 (1C),
137.21 (1C), 136.70 (1C), 129.43 (1C), 129.13 (1C), 128.91 (2C), 128.62 (2C), 127.99 (1C), 127.89 (1C),
127.63 (1C) 73.02 (1C), 66.89 (1C), 30.49 (1C), 28.53 (1C), 27.97 (1C); IR (neat) 3200 (br), 2970, 2934,
1748, 1684, 1595, 1411, 1208, 897, 746, 702 cm1. HR-MS [FAB(+)]: m/z calcd for C19H20NO3S [M+H]+
342.1164, found: 342.1198.
4-Methoxy-2,2-dimethyl-3-o-phenylbenzoylthiazolidine (2b)
Colorless oil, 58% yield.7 HPLC analysis was carried out using Daicel Chiralcel OD (0.46 cm x 50 cm);
n-hexane:2-propanol=30:1; wavelength, 210 nm; flow rate 0.5 mL/min; retention time, 30.1 min (major),
44.9 min (minor), 85.5% ee8; []26.7D –67.7 (c 0.5, CHCl3); 1H-NMR (300 MHz, CDCl3) 7.60-7.40 (m,
9H), 4.65 (d, 1H, J=3.0 Hz), 2.87 (s, 3H), 2.55 (d, 1H, J=12.4 Hz), 2.10 (dd, 1H, J=3.60, 12.4 Hz), 1.97 (s,
13
3H), 1.64 (s, 3H); C-NMR (100Hz, CDCl3)  169.41 (1C), 139.36 (1C), 137.94 (1C), 137.07 (1C),
129.50 (1C), 129.14 (1C), 128.98 (2C), 128.77 (1C), 128.61 (2C), 127.99 (1C), 127.48 (1C) 93.62 (1C),
71.75 (1C), 55.02 (1C), 33.10 (1C), 29.79 (1C), 28.44 (1C); IR (neat) 3050, 2977, 2930, 2828, 1657,
1605, 1580, 1478, 1372, 1182, 1073, 900, 891, 793, 747, 702 cm1. HR-MS [FAB(+)]: m/z calcd for
C19H22NO2S [M+H]+ 328.1371, found: 328.1389.
2,2,5,5-Tetramethyl-3-o-phenylbenzoylthiazolidine-4S-carboxylic acid (1c)
This procedure is similar to that of the preparation of 1a. 2,2,5,5-Tetramethylthiazolidine-4S-carboxylic
acid hydrochloride was reacted with o-phenylbenzoyl chloride in 200 mole equivaent of pyridine to
afford 3-(biphenyl-2-carbonyl)-2,2,5,5-tetramethylthiazolidine carboxylic acid 1c, 74% yield. White solid,
Mp 123-126 ˚C (uncorrected); []27.4D 59.9 (c 1.0, CHCl3); 1H-NMR (300 MHz, CDCl3)  7.70-7.26 (m,

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HETEROCYCLES, Vol. 80, No. 2, 2010
9H), 3.72 (s, 1H), 2.05 (s, 3H), 1.84 (s, 3H), 1.14 (s, 3H), 0.68 (s, 3H); IR (neat) 3200-2500, 2986, 2936,
13
1748, 1650, 1604, 1437, 1219 1165, 1129, 920, 768, 745, 702 cm1. C-NMR (100 MHz, CDCl3) 
174.46 (1C), 169.80 (1C), 139.12 (1C), 136.93 (1C), 136.66 (1C), 129.60 (2C), 129.20 (2C), 128.83 (2C),
128.25 (1C), 127.66 (1C), 127.08 (1C), 76.29 (1C) 73.87 (1C), 49.17 (1C), 32.25 (1C), 30.81 (1C), 28.64
(1C), 25.42 (1C); HR-MS [FAB(+)]: m/z calcd for C21H24NO3S [M+H]+ 370.1477, found: 370.1518.
4-Methoxy-2,2,5,5-tetramethyl-3-o-phenylbenzoylthiazolidine (2c)
Electrolysis of 1c using the general procedure described above furnished 2c, 54% yield. HPLC analysis of
2c was carried out using Daicel Chiralcel OD (0.46 cm x 25 cm); n-hexane:2-propanol=50:1;
wavelength, 210 nm; flow rate 0.5 mL/min; retention time, 14.2 min (minor), 28.3 min (major), 91% ee;
1
Mp 66-68 ˚C (uncorrected); []27.7 44.6 (c 0.5, CHCl3); H-NMR (300 MHz, CDCl3)  7.70-7.28 (m,
D
9H), 4.02 (s, 1H), 2.80 (s, 3H), 1.93 (s, 3H), 1.82 (s, 3H), 1.12 (s, 3H), 0.47 (s, 3H); IR (neat) 3050, 2924,
2853, 1655, 1466, 1387, 1182, 1223, 1073, 745, 702 cm1; Anal. Calcd for C21H25NO2S: C, 70.95; H,
7.09; N, 3.94. Found C: 71.01; H, 6.86; N, 3.60.
2,2,5-Trimethylthiazolidine-4R-carboxylic acid hydrochloride (D)
Disulfide B (268 mg, 1.0 mmol) prepared according to the reported procedure,5 was dissolved in MeOH
(4 mL), concentrated HCl (1.3 mL) added and zinc dust (600 mg) added in small portions with
continuous vigorous shaking. After reacting for 1.5 h, the undissolved zinc was filtered off and washed
o
with methanol. The combined filtrates were evaporated in vacuo at 30 C. The residue was dissolved in
acetone (20 mL) and refluxed for
4
h. Evaporation of the volatiles furnished
2,2,5R-trimethylthiazolidine-4S-carboxylic acid hydrochloride (C). 1H-NMR (CD3OD) 4.42 (1H, d, J=8.7
Hz); 4.04 (1H, dd, J=6.6, 9.0 Hz); 1.93 (3H, s); 1.66 (3H, d, J=6.3Hz).
2,2,5R-Trimethyl-3-o-phenylbenzoylthiazolidine-4R-carboxylic acid (1d)
A solution of the 2,2,5-trimethylthiazolidine-4R-carboxylic acid hydrochloride (C) in pyridine (37.1 mL,
464 mmol) at 0 C was added o-phenylbenzoyl chloride (501 mg, 2.32 mmol) dropwise. The mixture was
stirred at rt for 10 h, pyridine evaporated, residue dissolved in CH2Cl2 and the solution washed with 1%
HCl. The organic layer was dried over anhydrous MgSO4, filtered, evaporated in vacuo to afford a white
crystalline
material
which
was
purified
by
column
chromatography
to
furnish
2,2,5R-trimethyl-3-o-phenylbenzoylthiazolidine-4R-carboxylic acid (0.4mmol, 20% yield from B), Mp

1
199-202 C; []27.2 –171.4 (c 1.0, CH2Cl2); H-NMR (300 MHz, CDCl3)  7.64-7.26 (m, 9H), 3.90 (d,
D
1H, J=2.1Hz), 3.39 (dq, 1H, J=2.1, 7.2 Hz) 1.96 (s, 3H), 1.84 (s, 3H), 0.64 (d, 3H, J=7.2Hz); IR (neat)
3050, 2982, 2932, 1746, 1600, 1437, 1381, 1205, 1177, 1009, 912, 799, 745, 702 cm1; Anal. Calcd for

HETEROCYCLES, Vol. 80, No. 2, 2010
1185
C20H21NO3S: C, 67.58; H, 5.95; N, 3.94; S, 9.02. Found C: 67.96; H, 5.72; N, 3.98.
4-Methoxy-2,2,5R-trimethyl-3-o-phenylbenzoylthiazolidin (2d)
Electrolysis of 1d using the general procedure described above furnished a mixture of 2d as a single
diastereomer and the corresponding 4,5-dimethoxylated thiazolidine as an over-oxidized product in 38%
yield and 37% yield, respectively. Since it was very difficult to isolate chemically pure 2d from the
1
mixture, only H-NMR data of 2d is shown here. 2d: 1H-NMR (300 MHz, CDCl3)  7.60-7.28 (m, 9H),
4.20 (s, 1H), 3.02 (q, 1H, J=7.5Hz), 2.77 (s, 3H), 1.78 (s, 3H), 1.62 (s, 3H), 0.51 (s, 3H).
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