D-Penicillamine and L-cysteine derived thiazolidine catalysts: an efficient approach to both enantiomers of secondary alcohols

Article abstract of DOI:10.1016/j.tet.2016.08.036

D-Penicillamine derived thiazolidine ligands were prepared in a two-step synthetic sequence and used in the enantioselective alkylation of a variety of aromatic aldehydes with diethylzinc at room temperature. Excellent ee, up to >99%, and nearly complete conversions were observed. Structurally analogous L-cysteine derived thiazolidine ligands were also synthesized and tested for comparative purposes, resulting in very good, albeit slightly lower selectivities, up to 89%. The combined use of these two types of thiazolidines constitutes a very interesting strategy for synthesizing both (S) and (R) enantiomers of chiral secondary alcohols, thus leading the way to a myriad of useful optically active products with opposite absolute configurations.

Full text of DOI:10.1016/j.tet.2016.08.036

Accepted Manuscript
D-Penicillamine and L-cysteine derived thiazolidine catalysts: an efficient approach to
both enantiomers of secondary alcohols
M. Elisa Silva Serra, Dora Costa, Dina Murtinho, Nélia C.T. Tavares, Teresa M.V.D.
Pinho e Melo
PII:
S0040-4020(16)30812-2
10.1016/j.tet.2016.08.036
TET 28017
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 April 2016
Revised Date: 10 August 2016
Accepted Date: 12 August 2016
Please cite this article as: Serra MES, Costa D, Murtinho D, Tavares NCT, Pinho e Melo TMVD, D-
Penicillamine and L-cysteine derived thiazolidine catalysts: an efficient approach to both enantiomers of
secondary alcohols, Tetrahedron (2016), doi: 10.1016/j.tet.2016.08.036.
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ACCEPTED MANUSCRIPT
-Penicillamine and -Cysteine Derived Thiazolidine Catalysts:
D
L
An Efficient Approach to Both Enantiomers of Secondary Alcohols
M. Elisa Silva Serra*, Dora Costa, Dina Murtinho, Nélia C. T. Tavares, Teresa M. V. D. Pinho e
Melo
CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
e-mail: melisa@ci.uc.pt; tel: +0035139854480
Graphical abstract
1

ACCEPTED MANUSCRIPT
-Penicillamine and -Cysteine Derived Thiazolidine Catalysts:
D
L
An Efficient Approach to Both Enantiomers of Secondary Alcohols
M. Elisa Silva Serra*, Dora Costa, Dina Murtinho, Nélia C. T. Tavares, Teresa M. V. D. Pinho e
Melo
CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
e-mail: melisa@ci.uc.pt; tel: 0035139854480
Abstract: D-Penicillamine derived thiazolidine ligands were prepared in a two-step synthetic sequence and
used in the enantioselective alkylation of a variety of aromatic aldehydes with diethylzinc at room temperature.
Excellent ee, up to >99%, and nearly complete conversions were observed. Structurally analogous L-cysteine
derived thiazolidine ligands were also synthesized and tested for comparative purposes, resulting in very
good, albeit slightly lower selectivities, up to 89%. The combined use of these two types of thiazolidines
constitutes a very interesting strategy for synthesizing both (S) and (R) enantiomers of chiral secondary
alcohols, thus leading the way to a myriad of useful optically active products with opposite absolute
configurations.
Keywords: Asymmetric catalysis, Alkylation, Thiazolidine, L-Cysteine, D-Penicillamine
Introduction
Synthetic procedures for efficiently obtaining chiral secondary alcohols are of major importance due to the
vast application of these compounds in fine chemistry, pharmaceuticals, perfumes, herbicides, pesticides and
because these alcohols incorporate many structures with biological activity. There is also the purely synthetic
facet, since the hydroxyl group is an excellent precursor for many other functional groups, being very useful in
organic synthesis for obtaining a wide variety of chiral compounds. The enantioselective alkylation of aromatic
aldehydes with diethylzinc in the presence of chiral ligands is a versatile and extremely valuable synthetic
strategy for obtaining optically active secondary alcohols. Besides creating a new chiral center from the
carbonyl carbon, the reaction allows for the elongation of the carbon chain in the alcohol relatively to the
parent aldehyde.1–7
Many types of chiral ligands have been used in this process, namely, diamines and their derivatives, diols and
amino alcohols, among others giving products with high enantiomeric excesses.8,9 Ligands with cyclic or
bicyclic structures are especially good candidates as chiral ligands due to their rigid backbone structures.10–17
Chiral 1,3-thiazolidine-4-carboxylates derived from the naturally occurring amino acid L-cysteine have been
sparingly used for inducing chirality in the enantioselective alkylation of aldehydes with diethylzinc, originating
secondary alcohols with good to excellent enantiomeric excesses.18–23 These ligands are easily obtained in a
simple two-step synthetic sequence involving the esterification of L-cysteine followed by condensation with a
2

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carbonyl compound, aldehyde or ketone, to give a rigid five-membered heterocycle 1 (Scheme 1). To the best
of our knowledge, there is no reference of the use of structurally identical
2 (Scheme 1) in enantioselective alkylation reactions. These thiazolidines, easily obtained by a simple
process (similar to that already described), esterification of -penicillamine followed by condensation with the
carbonyl compound, could bring singular advantages to many catalytic processes.
The fact that -cysteine has a chiral center with (R) absolute configuration, while
D-penicillamine derived thiazolidines
D
L
D-penicillamine’s chiral
center has (S) absolute configuration, can allow attaining product alcohols with both (R) and (S) absolute
configurations when one or the other thiazolidine derivative is used, thus leading the way to a myriad of useful
optically active products with opposite absolute configurations.
Scheme 1
On the other hand, the two C5 methyl groups in D-penicillamine derived 2 may also have an influence on the
ee of the products formed in the alkylation reaction. The increased steric crowding, when combined with the
C2 substituents, may be either beneficial or detrimental.
In continuation of our studies on the enantioselective alkylation of aldehydes,24–28 we undertook the synthesis
of
D-penicillamine derived thiazolidines 2a-c and subsequently tested them in the enantioselective alkylation
of benzaldehyde with diethylzinc. Simultaneously, we synthesized structurally analogous
L
-cysteinederived
thiazolidines 1a-c in order to analyze the effect of the chiral center and of the steric hindrance on the
selectivity of the alkylation products.
Results and Discussion
D-Penicillamine was esterified with thionyl chloride and methanol, under reflux according to a previously
described procedure.29 In order to prepare thiazolidines 2b,c and 1b,c the
D
-penicillamine and -cysteine
L
methyl ester hydrochlorides were treated with triethylamine and then reacted with acetone or 3-pentanone in
the presence of a catalytic amount of TFA, under cyclohexane reflux for 18-24 h.23 Thiazolidines 1a and 2a
were obtained by reaction of the ester hydrochlorides with a formaldehyde solution in the presence of KHCO3,
ethanol/water (3:4) at room temperature overnight (Scheme 2).30
Scheme 2
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Using our previously established reaction conditions,24 we carried out the alkylation of benzaldehyde with
diethylzinc in cyclohexane, in an inert atmosphere and at room temperature. The results are presented in
Table 1.
Table 1. Enantioselective alkylation of benzaldehyde in the
presence of chiral thiazolidines 1-2.a
Entry Ligand
Conversion
(%)b
1-phenyl-1-propanol
(%)b
ee
(%)c
1
2
3
4
5
6
1a
1b
1c
2a
2b
2c
99
95
99
99
99
99
96
96
99
98
99
99
67 (S)
83 (S)
89 (S)
93 (R)
92 (R)
94 (R)
aReactions conditions: cyclohexane (4 mL), chiral ligand (0.15
mmol), benzaldehyde (1 mmol), diethylzinc solution 1M in hexane
(2 mmol), 24 h, room temperature. bDetermined by GC.
cDetermined by GC on a chiral column; the major enantiomer is
indicated in parenthesis.
All of the thiazolidines tested gave nearly complete conversion of benzaldehyde to the corresponding
secondary alcohol. Thiazolidines 2 gave products with excellent ee (92-94%), while thiazolidines 1 gave good
ee (67-89%), indicating that the former are much more efficient chiral inducers in these reactions, under our
optimized conditions.
The results observed with 2 indicate that the most important steric factor here seems to be the two C5 methyl
groups, while the C2 substituents do not appear to significantly contribute to the chiral induction by these
thiazolidines. On the other hand, the C2 substituents on thiazolidines 1 do have a significant effect on the
chiral induction capacity of these ligands. 1c, the most sterically encumbered ligand, with two ethyl groups at
C2, gave 1-phenyl-1-propanol with the highest ee of this series, 89%.
As was initially expected, due to the opposite stereochemistry of the chiral C4 of the ligands, the two series
originated products with opposite absolute configuration, creating a very useful system for obtaining both
enantiomers of secondary alcohols.
Proline and pyrrole esters are referred to present bidentate coordination, namely, through the carbonyl oxygen
and the ring nitrogen atom.31–33 It is believed that thiazolidine esters also coordinate in a similar bidentate
manner. We decided to evaluate the effect on the selectivity of the process, of the presence of an additional
coordinating atom on the thiazolidine, which could open the way to new interesting derivatives. For this study
we synthesized
L-cysteine derived thiazolidines 3a-3c. For the same purpose, we also synthesized the
corresponding D-penicillamine derivatives 4a-c (Scheme 3). These aldehyde-derived thiazolidines are formed
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as diastereoisomeric mixtures with respect to C2. In solution these diastereoisomers interconvert through a
mechanism involving opening of the thiazolidine ring.34,35
It has been observed that the existence of the two diastereoisomers, in itself, does not affect the selectivity in
enantioselective reactions using this type of ligands. This has been explained as resulting from different
characteristics, namely, significantly different rates of reaction of the two diastereoisomeric catalysts or lack of
coordination of one of the diastereoisomers.21,36,37
Scheme 3
The ethyl ester of 3a has been previously used in the enantioselective alkylation of benzaldehyde, giving a
product with 80% ee.21 We synthesized the methyl ester (Table 2, ee 75%) for comparative purposes, since
all thiazolidines used in our studies are methyl esters. The tridentate ligand 3b was synthesized by
condensation of the cysteine methyl ester hydrochloride with salicylaldehyde.38 In the alkylation of
benzaldehyde with ZnEt2, this ligand led to moderate conversion and low ee, 10% (Table 2, entry 2). This
clearly demonstrates the negative effect of the presence of the hydroxyl group. In order to clarify whether this
result is due to coordination or simply to additional steric volume close to the coordinating atoms, we
synthesized yet another derivative 3c, with a methoxy instead of a hydroxyl group. The higher conversion and
ee observed with this ligand (Table 2, entry 3) seem to indicate that the low performance of 3b may be due to
an unfavorable tridentate coordination. An alternative mode of bidentate coordination to the zinc, involving the
nitrogen and the hydroxyl instead of the ester, is also plausible.
Table 2. Enantioselective alkylation of benzaldehyde in the
presence of chiral thiazolidines 3-4.a
Entry
Ligand Conversion
(%)b
1-phenyl-1-propanol
(%)b
ee
(%)c
1
2
3
4
5
6
3a
3b
3c
4a
4b
4c
92
77
98
78
95
97
90
99
75 (S)
10 (S)
57 (S)
87 (R)
11 (R)
84 (R)
91
95
92
>99
aReactions conditions: cyclohexane (4 mL), chiral ligand (0.15
mmol), benzaldehyde (1 mmol), diethylzinc solution 1M in hexane
(2 mmol), 24 h, room temperature. bDetermined by GC.
cDetermined by GC on a chiral column; the major enantiomer is
indicated in parenthesis.
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We additionally synthesized the analogous penicillamine derived ligands 4a-c. A similar trend was observed in
the enantioselective alkylation of benzaldehyde with these ligands (Table 2, entries 4-6). Once again the
hydroxyl containing ligand gave the product alcohol with low ee, while the methoxy derivative 4c gave the
product with 85% ee. The results observed with 3 and 4 seem to indicate that coordination of the thiazolidines
to the zinc atom by the nitrogen atom and ester group favors chiral induction.
Using D-penicillamine derived thiazolidine 2a, we carried out the alkylation of several other aromatic
aldehydes with ZnEt2, in order to assess the scope of these ligands. The results of this study are presented in
Table 3. All aldehydes suffered complete conversion to the product alcohol, except for p-anisaldehyde (97%).
The ee of the chiral alcohols, 86 to >99%, prove the excellent performance of the ligand, covering a range of
aromatic phenyl substrates with both electron-donating and electron-withdrawing substituents, as well as
naphthaldehyde.
Table 3. Enantioselective alkylation of aromatic aldehydes in
the presence of chiral thiazolidine 2a.a
Entry
Aldehyde
Conversion
(%)b
ee
(%)c
1
2
3
4
5
6
7
8
9
benzaldehyde
o-methylbenzaldehyde
p-methylbenzaldehyde
o-anisaldehyde
>99
>99
>99
>99
>99
97
95 (R)
89 (R)
95 (R)
98 (R)
>99 (R)
>99 (R)
86 (R)
91 (R)
97 (R)
m-anisaldehyde
p-anisaldehyde
o-chlorobenzaldehyde
p-chlorobenzaldehyde
1-naphthaldehyde
>99
>99
99
aReactions conditions: cyclohexane (4 mL), chiral ligand
(0.15 mmol), aldehyde (1 mmol), diethylzinc solution 1M in
b
hexane (2 mmol), 24 h, room temperature. Determined by
GC. cDetermined by GC on a chiral column; the major
enantiomer is indicated in parenthesis.
We tested heteroaromatic furfural and aliphatic cinnamaldehyde, phenylacetaldehyde and octanal as
substrates as well, in the presence of 2a, in order to further assess the scope of our ligands (Table 4). At room
temperature, almost complete conversions were observed except for phenylacetaldehyde and ee varied from
24% to 80%, the best result being obtained in the alkylation of octanal. Considering the high activity of the
catalyst, we decided to lower the temperature to 0ºC (Table 4, entries 2, 3, 5) and found that there was no
significant change in yield and a small increase in the ee of the products. A further decrease in temperature to
-10 ºC in the case of cinnamaldehyde also had no effect on either conversion or ee.
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Table 4. Enantioselective alkylation of cinnamaldehyde and
furfural in the presence of chiral thiazolidine 2a.a
Conversion
(%)b
ee
Entry
Aldehyde
Temperature
(%)c
1
2
3
rt
99
>99
96
47
56
56
0 ºC
-10 ºC
4
5
rt
>99
>99
56
60
0 ºC
6
rt
30
24
7
rt
99
80d
aReactions conditions: cyclohexane (4 mL), chiral ligand (0.15 mmol),
aldehyde (1 mmol), diethylzinc solution 1M in hexane (2 mmol), 24 h.
bDetermined by GC. cDetermined by GC on a chiral column. dDetermined
by polarimetry.
Conclusions
Using a simple two-step synthetic sequence three D-penicillamine derived chiral thiazolidine ligands were
prepared through condensation with ketones and aldehydes. Using our most selective ligand, products with
excellent selectivity, up to >99 % ee of the (R) enantiomer, were obtained in the alkylation of aromatic
aldehydes with diethylzinc at room temperature. When the ligand was used in the enantioselective alkylation
of hetero- and non-aromatic aldehydes, ee of up to 80% were observed, which are interesting values for these
types of substrates.
Analogous
giving up to 89% ee of the (S) enantiomer, demonstrate that it is possible to efficiently and selectively obtain
both enantiomers of chiral secondary alcohols. The combined use of both -penicillamine and -cysteine
L-cysteine derived thiazolidines, also synthesized and tested in the alkylation of benzaldehyde,
D
L
derived thiazolidines constitutes a very interesting strategy that can lead to the synthesis of a great variety of
chiral compounds having opposite absolute configurations, with potential applications in fine chemistry.
Experimental Section
General
Commercially available compounds were used without further purification. All solvents were dried prior to use
following standard procedures. Diethylzinc (Aldrich) was used as a 1M solution in hexane. Benzaldehyde was
distilled prior to use and stored over 4 Å molecular sieves. Melting points were determined using a FALC
melting point apparatus (open capillary method). Optical rotations were measured with an Optical Activity AA-
5 polarimeter. NMR spectra were recorded at room temperature on a Bruker Avance III 400 MHz (100 MHz
for 13C). TMS was used as the internal standard and chemical shifts are given in ppm. Infrared spectra were
recorded on a Thermo Scientific Nicolet 6700 FTIR. High-resolution mass spectra (HRMS) were obtained on a
TOF VG Autospect M spectrometer with electrospray ionization (ESI).
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Alkylation reactions were carried out in an inert atmosphere using standard Schlenk-type techniques.
Enantiomeric excesses were determined by using a chiral γ-cyclodextrin capillary column (FS-Lipodex-E, 25
m, 0.25 i.d.) from Machery-Nagel using hydrogen as carrier gas, on an Agilant 7820 instrument (for the
phenylacetadehyde product, a β-cyclodextrin capillary column was used). The configuration of the major
enantiomers was determined by comparison of the retention times with reported values and by determining
the sign of the optical rotation of the isolated reactions. The ee of 3-decanol was determined by polarimetry
([α] 2D1 = + 9.95 (c3.96, pentane).39
Thiazolidines 1a28 1b29 1c13 3a23 3b38 4a40,41 were prepared according to adapted literature procedures and
presented spectroscopic data in agreement with that described. D-Penicillamine methyl ester hydrochloride
was prepared according to a described procedure and used directly.29
General procedure for the synthesis of thiazolidines 2b, 2c:
To the (S)-penicillamine methyl ester hydrochloride (3 mmol, 0.60 g) in dry cyclohexane (10 mL), triethylamine
(3 mmol, 0.42 mL) was added, followed by the ketone (2.7 mmol) and 2-3 drops of TFA. The reaction was
refluxed for 24 h. The resulting suspension was filtered, the residue was washed with ether and the combined
filtrates were evaporated to give the thiazolidine, which was purified as described below.
(S)-methyl 2,2,5,5-tetramethylthiazolidine-4-carboxylate (2b): The product was purified by alumina column
chromatography using ethyl acetate:hexane (1:2) as eluent to give a white solid, mp: 34-36 ºC. Yield: 55%. [α]
20 = +122 (c1.06, CH2Cl2). IR (KBr, cm-1): 2966, 2920, 1743, 1456, 1439, 1379, 1369, 1342, 1279, 1225,
D
1196, 1180, 1144, 1115, 1028, 1007. 1H NMR (CDCl3): δ = 1.21 (s, 3H); 1.54 (s, 3H); 1.62 (s, 3H); 1.66 (s,
3H); 3.76 (s, 3H); 4.02 (s, 1H); 4.87 (bs, 1H); 13C NMR: δ = 27.9; 28.9; 32.0; 33.4; 52.1; 61.1; 72.7; 73.0;
170.0. HRMS (ESI): calcd. for C9H18NO2S [M+H]+ 204.1053; found [M+H]+ 204.1058.
(S)-methyl 2,2-diethyl-5,5-dimethylthiazolidine-4-carboxylate (2c): The product was purified by alumina
column chromatography using an ethyl acetate:hexane gradient as eluent (1:2 to ethyl acetate) to give a
colorless oil. Yield: 35%. [α] 2D0 = +83 (c0.67, CH2Cl2). IR (KBr, cm-1): 2966, 2931, 2879, 1745, 1456, 1435,
1367, 1338, 1321, 1261, 1219, 1196, 1173, 1124, 1107. 1H NMR (CDCl3): δ = 0.90 (t, J=7.4 Hz); 1.01 (t, J=7.4
Hz); 1.19 (s, 3H); 1.60 (s, 3H); 1.71-1.93 (m, 4H); 3.04 (bs, 1H); 3.76 (s, 3H); 3.86 (s, 1H). 13C NMR: δ = 9.5;
9.9; 27.9; 28.7; 32.8; 34.9; 52.0; 58.9; 72.7; 81.6; 170.3. HRMS (ESI): calcd. for C11H22NO2S [M+H]+
232.1366; found [M+H]+ 232.1362.
General procedure for the synthesis of thiazolidines 1a, 2a:
To the penicillamine or cysteine methyl ester hydrochloride (1.5 mmol, 0.30 g) in ethanol/water (3:4), (7 mL)
KHCO3 (1.5 mmol, 0.15 g) was added, followed by a 37% formaldehyde solution (1.35 mmol, 0.11 mL). The
reaction was stirred at room temperature until complete. Water (10 mL) was added and the mixture was
extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium
sulfate, filtered and evaporated to give the thiazolidine, which was purified as described below.
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General procedure for the synthesis of thiazolidines 4a-c:
To the penicillamine or cysteine methyl ester hydrochloride (1.5 mmol, 0.30 g) in ethanol/water (3:4), (7 mL)
NEt3 (1.5 mmol, 0.24 mL) was added, followed by the aldehyde (1.5 mmol). The reaction was stirred at room
temperature until complete. Water (10 mL) was added and the mixture was extracted three times with
dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and
evaporated to give the thiazolidine, which was purified as described below.
(S)-methyl 5,5-dimethylthiazolidine-4-carboxylate (2a): The reaction was complete after 18 h. The product
was purified by alumina column chromatography using ethyl acetate:hexane (1:2) as eluent to give a low
melting white solid. Yield: 46%. [α] 2D0 = +46 (c0.99, CH2Cl2). IR (KBr, cm-1): 3419, 2956, 2933, 2873, 2708,
2542, 1747, 1456, 1441, 1396, 1375, 1311, 1246. 1H NMR (CDCl3): δ = 1.21 (s, 3H); 1.65 (s, 3H); 3.50 (s,
1H); 3.77 (s, 3H); 4.27 (dd, J= 10 Hz, 50 Hz, 2H). 13C NMR: δ = 27.9; 29.1; 52.1; 52.3; 57.8; 74.6; 170.1.
HRMS (ESI): calcd. for C7H14NO2S [M+H]+ 176.0740; found [M+H]+ 176.0739.
(S)-methyl 2-(2-hydroxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4b): The reaction was
complete after 48 h. The product (a mixture of diastereoisomers) was purified by silica gel chromatography,
using ethyl acetate as eluent, and obtained as a dark orange oil, with quantitative yield. [α] 2D0 = +174 (c1.15,
CH2Cl2). IR (KBr, cm-1): 3288, 3048, 2964, 2928, 2867, 1735, 1719, 1707, 1624, 1618, 1587, 1578, 1487,
1457, 1437, 1388, 1368, 1320, 1275, 1254, 1210, 1184, 1126, 1098, 1033, 1015, 999, 927, 875, 850, 751. 1H
NMR (CDCl3): δ = 1.32, 1.38 (s, 3H); 1.61, 1.73 (s, 3H); 2.17 (s, 1H); 3.75, 3.77 (s, 1H); 3.79, 3.81 (s, 3H);
5.70, 6.00 (s, 1H); 6.80-6.92 (m, 2H); 7.14-7.26 (m, 2H). 13C NMR: δ = 27.1, 28.2, 28.8, 29.9, 52.3, 52.5, 57.2,
58.0, 66.9, 71.5, 73.4, 117.1, 117.3, 119.4, 119.9, 122.0, 123.2, 123.3, 128.7, 129.4, 130.2, 155.9, 156, 169.3,
169.7. HRMS (ESI): calcd. for C13H18NO3S [M+H]+ 268.1002; found [M+H]+ 268.0997.
(S)-methyl 2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4c): The reaction was
complete after 6 days. The product (a mixture of diastereoisomers) was purified by silica gel chromatography,
using ethyl acetate:hexane (1:5) as eluent, giving a light yellow oil, with quantitative yield. [α] 2D0 = +100 (c1,
CH2Cl2). IR (KBr, cm-1): 3338, 2955, 2925, 2837, 1735, 1719, 1600, 1588, 1488, 1458, 1437, 1434, 1367,
1323, 1289, 1260, 1241, 1202, 1183, 1157, 1122, 1099, 1048, 1023, 1000, 929, 841, 778, 751, 669. 1H NMR
(CDCl3): δ = 1.30, 1.34 (s, 3H); 1.57, 1.71 (s, 3H); 3.67, 3.75 (s, 1H); 3.79, 3.80 (s, 3H); 3.84, 3.87 (s, 3H);
5.97, 6.00, 6.01 (s, 1H); 6.83-6.99 (m, 2H); 7.19-7.31 (m, 1H); 7.50-7.55 (m, 1H). 13C NMR: δ = 27.3, 27.4,
28.4, 29.1, 52.0, 52.1, 55.3, 55.6, 57.9, 59.091 63.1, 65.2, 73.2, 74.8, 110.4, 111.1, 120.4, 120.8, 124.9,
126.4, 128.0, 128.2, 129.6, 131.9, 156.4, 157.3, 169.9, 170.3. HRMS (ESI): calcd. for C14H20NO3S [M+H]+
282.1158; found [M+H]+ 282.1154.
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General procedure for the synthesis of thiazolidines 1b, 1c, 3c:
To (R)-cysteine methyl ester hydrochloride (25 mmol, 4.29 g) in dry cyclohexane (50 mL), triethylamine (25
mmol, 3.49 mL) was added, followed by the aldehyde or ketone (22.5 mmol) and 2-3 drops of TFA. The
reaction was refluxed for 24 h. The resulting suspension was filtered, the residue was washed with ether and
the combined filtrates were evaporated to give the thiazolidine, which was purified as described below.
(R)-methyl 2-(2-methoxyphenyl)thiazolidine-4-carboxylate (3c): The product (a mixture of
diastereoisomers) was purified by silica gel column chromatography using ethyl acetate:hexane (1:2) as
eluent to give a pale yellow oil. Yield: 77%. [α] 2D0 = -120 (c1.29, CH2Cl2). IR (KBr, cm-1): 2951, 2837, 1743,
1601, 1587, 1489, 1464, 1437, 1362, 1327, 1296, 1267, 1248, 1203, 1171, 1161, 1122, 1107, 1088, 1049,
1026, 831, 793, 756. 1H NMR (CDCl3): δ = 3.03–3.24 (m, 1H); 3.40–3.45 (m, 1H); 3.81 (s, 3H); 3.87, 3.88 (s,
3H); 3.95 (bs, 1H); 5.58, 6.01 (s, 1H); 6.86–7.00 (m, 2H); 7.24–7.42 (m, 2H); 7.43–7.51 (m, 2H). 13C NMR: δ =
37.7, 39.0, 52.5, 52.6, 55.5, 55.7, 64.9, 65.7, 65.9, 67.7, 110.7, 111.1, 120.5, 120.8, 125.8, 126.0, 127.8,
128.7, 129.7, 130.0. HRMS (ESI): calcd. for C12H16NO3S [M+H]+ 254.0845; found [M+H]+ 254.0846.
General procedure for enantioselective alkylations
To the chiral ligand (0.15 mmol) and aldehyde (1 mmol) in an inert atmosphere, 4 mL of dry cyclohexane were
added. The temperature of the reaction mixture was lowered to 0º C and diethylzinc (2 mmol, 2 mL, as a 1M
hexane solution) was added. The reaction was stirred 10 min at 0 ºC and then for 24 h at the required
temperature. Subsequently, a saturated ammonium chloride solution (1 mL) was added, followed by 2M HCl
(1 mL) and the reaction mixture was extracted with diethyl ether. The joint organic phases were washed with
water and brine and dried over anhydrous sodium sulfate. The resulting solution was analyzed by GC on a
chiral γ-cyclodextrin capillary column in order to determine the ee of the products.24
Acknowledgements
The authors thank the FCT (projects Pest-C/QUI/UI0313/2011 and PEstOE/QUI/UI0313/2014), FEDER,
COMPETE and QREN for financial support (including Dora Costa grant UI0117/QUI/UI0113/2014) and the
UC-NMR facility for NMR spectroscopic data (FCT, grant numbers REEQ/481/QUI/2006,
RECI/QEQQFI/0168/2012, CENTRO-07-CT62-FEDER-002012 and RNRMN, FEDER and COMPETE).
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SCHEMES
Scheme 1
Scheme 2
Scheme 3
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TABLES
Table 1. Enantioselective alkylation of benzaldehyde in the
presence of chiral thiazolidines 1-2.a
Entry Ligand
Conversion
(%)b
1-phenyl-1-propanol
(%)b
ee
(%)c
1
2
3
4
5
6
1a
1b
1c
2a
2b
2c
99
95
99
99
99
99
96
96
99
98
99
99
67 (S)
83 (S)
89 (S)
93 (R)
92 (R)
94 (R)
aReactions conditions: cyclohexane (4 mL), chiral ligand (0.15
mmol), benzaldehyde (1 mmol), diethylzinc solution 1M in hexane
(2 mmol), 24 h, room temperature. bDetermined by GC.
cDetermined by GC on a chiral column; the major enantiomer is
indicated in parenthesis.
Table 2. Enantioselective alkylation of benzaldehyde in the
presence of chiral thiazolidines 3-4.a
Entry
Ligand Conversion
(%)b
1-phenyl-1-propanol
(%)b
ee
(%)c
1
2
3
4
5
6
3a
3b
3c
4a
4b
4c
92
77
98
78
95
97
90
99
75 (S)
10 (S)
57 (S)
87 (R)
11 (R)
84 (R)
91
95
92
>99
aReactions conditions: cyclohexane (4 mL), chiral ligand (0.15
mmol), benzaldehyde (1 mmol), diethylzinc solution 1M in hexane
(2 mmol), 24 h, room temperature. bDetermined by GC.
cDetermined by GC on a chiral column; the major enantiomer is
indicated in parenthesis.
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Table 3. Enantioselective alkylation of aromatic aldehydes in
the presence of chiral thiazolidine 2a.a
Entry
Aldehyde
Conversion
(%)b
ee
(%)c
1
2
3
4
5
6
7
8
9
benzaldehyde
o-methylbenzaldehyde
p-methylbenzaldehyde
o-anisaldehyde
>99
>99
>99
>99
>99
97
95 (R)
89 (R)
95 (R)
98 (R)
>99 (R)
>99 (R)
86 (R)
91 (R)
97 (R)
m-anisaldehyde
p-anisaldehyde
o-chlorobenzaldehyde
p-chlorobenzaldehyde
1-naphthaldehyde
>99
>99
99
aReactions conditions: cyclohexane (4 mL), chiral ligand
(0.15 mmol), aldehyde (1 mmol), diethylzinc solution 1M in
b
hexane (2 mmol), 24 h, room temperature. Determined by
GC. cDetermined by GC on a chiral column; the major
enantiomer is indicated in parenthesis.
Table 4. Enantioselective alkylation of cinnamaldehyde and
furfural in the presence of chiral thiazolidine 2a.a
Conversion
(%)b
ee
Entry
Aldehyde
Temperature
(%)c
1
2
3
rt
99
>99
96
47
56
56
0 ºC
-10 ºC
4
5
rt
>99
>99
56
60
0 ºC
6
rt
rt
30
99
24
7
80d
aReactions conditions: cyclohexane (4 mL), chiral ligand (0.15 mmol),
aldehyde (1 mmol), diethylzinc solution 1M in hexane (2 mmol), 24 h.
bDetermined by GC. cDetermined by GC on a chiral column. dDetermined
by polarimetry.
15