Chiral thiazolidines in the enantioselective ethylation of aldehydes: An experimental and computational study

Article abstract of DOI:10.1016/j.jorganchem.2018.09.027

A library of new chiral thiazolidines was prepared starting from L-cysteine and D-penicillamine in a simple, one-step procedure. 2-Arylthiazolidines were obtained, as diastereoisomeric mixtures, with good yields and in short reaction times, through a new and greener procedure, using microwave irradiation. Their use as chiral ligands in the enantioselective ethylation of aromatic aldehydes was studied and optimized, originating good to excellent conversions and ee up to 94% in 6 h. A series of heteroaromatic and aliphatic substrates were also enantioselectively ethylated with success, with ee up to 77%. The distinct opposite chirality in L-cysteine and D-penicillamine makes the use of these ligands an interesting approach for obtaining both the (S) and (R) enantiomers of the chiral alcohols, compounds with potential applications in the area of fine chemistry. NMR studies were carried out using a diastereoisomeric mixture of thiazolidines, allowing the identification of the most stable structure. Computational studies confirmed this result and also gave important insight into the species involved in the catalytic cycle of the enantioselective alkylation.

Full text of DOI:10.1016/j.jorganchem.2018.09.027

Accepted Manuscript
Chiral thiazolidines in the enantioselective ethylation of aldehydes: An experimental
and computational study
Nélia C.T. Tavares, César T. Neves, Bruce F. Milne, Dina Murtinho, Alberto A.C.C.
Pais, M. Elisa Silva Serra
PII:
S0022-328X(18)30769-1
10.1016/j.jorganchem.2018.09.027
JOM 20584
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 3 September 2018
Revised Date: 26 September 2018
Accepted Date: 30 September 2018
Please cite this article as: Né.C.T. Tavares, Cé.T. Neves, B.F. Milne, D. Murtinho, A.A.C.C. Pais,
M.E.S. Serra, Chiral thiazolidines in the enantioselective ethylation of aldehydes: An experimental
and computational study, Journal of Organometallic Chemistry (2018), doi: https://doi.org/10.1016/
j.jorganchem.2018.09.027.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Chiral Thiazolidines in the Enantioselective Ethylation of Aldehydes: An
Experimental and Computational Study
Nélia C. T. Tavares, César T. Neves, Bruce F. Milne, Dina Murtinho, Alberto A. C. C. Pais and
M. Elisa Silva Serra*

ACCEPTED MANUSCRIPT
Chiral Thiazolidines in the Enantioselective Ethylation of Aldehydes: An
Experimental and Computational Study
Nélia C. T. Tavares[a], César T. Neves[a], Bruce F. Milne[a], Dina Murtinho[a], Alberto A. C. C.
Pais[a] and M. Elisa Silva Serra*[a]
[a]CQC and Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal
E-mail: melisa@ci.uc.pt
Abstract
A library of new chiral thiazolidines was prepared starting from L-cysteine and D-penicillamine in
a simple, short synthetic sequence. 2-Arylthiazolidines were obtained, as diastereoisomeric
mixtures, with good yields and in short reaction times, through a new and greener procedure,
using microwave irradiation. Their use as chiral ligands in the enantioselective ethylation of
aromatic aldehydes was studied and optimized, originating good to excellent conversions and
ee up to 94% in 6 hours. A series of heteroaromatic and aliphatic substrates were also
enantioselectively ethylated with success, with ee up to 77%. The distinct opposite chirality in
L-
cysteine and -penicillamine makes the use of these ligands an interesting approach for
D
obtaining both the (S) and (R) enantiomers of the chiral alcohols, compounds with potential
applications in the area of fine chemistry. NMR studies were carried out using a
diastereoisomeric mixture of thiazolidines, allowing the identification of the most stable
structure. Computational studies confirmed this result and also gave important insight into the
species involved in the catalytic cycle of the enantioselective alkylation.
Keywords
Alkylation; asymmetric catalysis; microwave synthesis; thiazolidine; computational studies.
Introduction
One of the most crucial reactions in organic chemistry is the formation of carbon-carbon bonds.
The alkylation of aldehydes to obtain secondary alcohols is included in this type of reaction.
Synthetic approaches to develop the asymmetric version of this reaction have been improved
over time, since the use of lithium organometallics in 1978 by Soai et.al.[1] Nowadays, the use
of zinc organometallics, especially diethylzinc, is one of the most frequently used methods. The
addition of diethylzinc to aldehydes in order to form chiral alcohols can only occur through
ligand activation. When the ligand is chiral, the reaction allows the discrimination of the two
enantiotopic faces of the aldehyde, thus leading to chiral secondary alcohols. These
compounds, besides their presence in several naturally occurring molecules and liquid crystals,
have a wide application in fine chemistry, integrating the composition of biologically active
molecules such as drugs, perfumes, agrochemicals, pesticides, herbicides and pheromones.
From the synthetic point of view, the hydroxyl group can be an excellent precursor of several
other types of functional groups.[2–8] Several types of chiral ligands have successfully been

ACCEPTED MANUSCRIPT
used in this reaction, namely aminoalcohols, diamines, diols and their derivatives, affording the
chiral products with good enantiomeric excesses.[9–24] Also reported are the advantages of
using molecules with rigid cyclic structures, as their presence allows the formation of a more
hindered and rigid catalyst, that allows better discrimination of the two possible transition state
structures.[25–30] Although there are many ligands capable of catalyzing this reaction, research
focused on the development of new active, enantioselective, easily synthesized and
economically viable catalysts continues.
From the condensation of the methyl esters of
L-cysteine and D-penicillamine with
carbonyl compounds, aldehydes or ketones, it is possible to obtain chiral thiazolidines.[31]
These compounds were found to act as efficient catalysts in enantioselective alkylation
reactions, providing good to excellent enantiomeric excesses.[32–35] In previous studies, we
observed better results when using thiazolidines derived from
to the -cysteine analogs, possibly due to the more hindered C5 position, with two methyl
groups.[36]
D-penicillamine when compared
L
Continuing our previous studies, we undertook the synthesis of a series of new C2-
aromatic substituted thiazolidines from L-cysteine and D-penicillamine. A new and greener
protocol for the synthesis of the thiazolidines was developed, simpler than the usual
conventional methods. The thiazolidines were tested as ligands in the enantioselective
alkylation of aldehydes with diethylzinc. The effect of different aromatic groups at C2 was
evaluated. Aromatic groups where the same substituent was located in the ortho, meta or para
positions were used in order to evaluate the steric effect, while electron-donating and electron-
withdrawing substituents were used to analyze the resulting electronic effect on the outcome of
the reaction. Additionally, computational and NMR studies were carried out, allowing us to
understand the relative stability of the thiazolidine diastereoisomers and the structures of some
of the species involved in the catalytic cycle of the enantioselective alkylation with diethylzinc.
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 1 M
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 an Agilent Technologies Cary 630 FTIR in the ATR mode. High-resolution
mass spectra (HRMS) were obtained on a TOF VG Autospect M spectrometer with electrospray
ionization (ESI). Elemental analyses were carried out on an Elementar Vario Micro Cube
analyser. Microwave reactions were carried out in a CEM Discover S-Class instrument.

ACCEPTED MANUSCRIPT
Alkylation reactions were carried out in an inert atmosphere using standard Schlenk-type
techniques. Enantiomeric excesses and conversions were determined using a chiral γ-
cyclodextrin capillary column (FS-Lipodex-E, 25 m, 0.25 i.d.) from Machery-Nagel, on an Agilant
7820 instrument, using hydrogen as carrier gas. The configuration of the major enantiomers
was determined by comparison of the retention times with reported values and by determining
the sign of the specific rotation of the isolated products.[37–42]
General procedure for the synthesis of thiazolidines 3 and 4
In a microwave reaction tube L-cysteine methyl ester hydrochloride 1 or D-penicillamine methyl
ester hydrochloride 2 (5.00 mmol, 0.858 g or 0.998 g, respectively), were dissolved in distilled
water (5 mL). To this solution, triethylamine (5.00 mmol, 0.69 mL) and the aldehyde (5.00 mmol)
were added. The reaction mixture was subjected to microwave irradiation, using a temperature
control program (100 C) for 15 minutes. Subsequently, upon cooling, water was added to the
reaction mixture, followed by extraction with dichloromethane (3 times). The organic phases
were combined, dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The resulting mixture was purified as described below.
(4R)-Methyl 2-(2-methoxyphenyl)-1,3-thiazolidine-4-carboxylate (3a) and (4S)-Methyl 2-(2-
methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4a) were prepared in 85% and
83% yield, respectively, using microwave irradiation and spectroscopic data are in agreement
with those previously described.[36]
(4R)-Methyl 2-(3-methoxyphenyl)-1,3-thiazolidine-4-carboxylate (3b). The product was purified
by silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a pale
yellow oil. Yield: 71%. [α]ꢁꢀꢂ= -92.7 (c 1.03, CH2Cl2). IR (ATR, cm-1): 3313, 2951, 2836, 1735,
1
1598, 1584, 1488, 1433, 1258, 1202, 1153, 1037, 781, 757, 697. H NMR (CDCl3): (mixture of
diastereoisomers) δ= 2.67/2.84 (two bs, 1H), 3.10/3.18 (two dd, J = 9.0, 10.3 Hz / J = 5.8, 10.7
Hz, 1H), 3.38/3.45 (two dd, J = 7.2, 10.7 Hz / J = 7.2, 10.3 Hz, 1H), 3.78/3.80/3.81 (three s, 6H),
3.97/4.21 (two aprox. t, J = 7.8 Hz / J = 6.4 Hz, 1H), 5.53/5.79 (two s, 1H), 6.79-6.81/6.85-6.88
(two m, 1H), 7.04 – 7.11 (m, 2H), 7.22 – 7.30 (m, 1H). 13C NMR: δ= 38.0, 39.0, 52.4, 52.4, 55.1,
55.2, 64.2, 65.4, 70.6, 72.4, 112.3, 112.9, 113.3, 114.1, 119.1, 119.6, 129.3, 129.6, 139.7,
142.8, 159.6, 159.7, 171.5, 172.1. HRMS (ESI): calcd for C12H15NO3S [M+H]+ 254.0845; found
[M+H]+ 254.0853.
(4R)-Methyl 2-(4-methoxyphenyl)-1,3-thiazolidine-4-carboxylate (3c). The product was purified
by silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a pale
yellow oil. Yield: 68%. [α]ꢁꢀꢂ= -95.0 (c 1.00, CH2Cl2). IR (ATR, cm-1): 3306, 2951, 2837, 1735,
1610, 1509, 1437, 1243, 1172, 1159, 1029, 808, 767. 1H NMR (CDCl3): (mixture of
diastereoisomers) δ= 2.60/2.75 (two bs, 1H), 3.10/3.22 (two dd, J = 9.0, 10.2 Hz / J = 5.6, 10.8
Hz, 1H), 3.39/3.45 (two dd, J = 7.2, 10.8 Hz / J = 7.0, 10.2 Hz, 1H), 3.78/3.79/3.80/3.80 (four s,
6H), 3.96-3.98/4.23 (m / aprox. t, J = 6.4 Hz, 1H), 5.52/5.76 (d, J= 7.2 Hz / s, 1H), 6.83 – 6.91

ACCEPTED MANUSCRIPT
(m, 2H), 7.39 – 7.46 (m, 2H). 13C NMR: δ= 38.1, 39.3, 52.6, 52.6, 55.3, 55.3, 64.3, 65.5, 70.6,
72.3, 113.8, 114.0, 128.3, 128.7, 130.1, 132.9, 159.3, 159.9, 171.7, 172.3. HRMS (ESI): calcd
for C12H15NO3S [M+H]+ 254.0845; found [M+H]+ 254.0850.
(4R)-Methyl 2-(2-chlorophenyl)-1,3-thiazolidine-4-carboxylate (3d). The product was purified by
silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a pale
yellow oil. Yield: 71%. [α]ꢁꢀꢂ= -150.8 (c 1.00, CH2Cl2). IR (ATR, cm-1): 3327, 2951, 1735, 1437,
1320, 1265, 1225, 1201, 1173, 1158, 1034, 823, 743. 1H NMR (CDCl3): (mixture of
diastereoisomers) δ= 3.07-3.14 (m, 1H), 3.34/3.47 (two dd, J= 6.6, 10.6 Hz / J= 6.8, 10.4 Hz,
1H), 3.81/3.82 (two s, 3H), 3.98-4.05/4.24-4.25 (two m, 1H), 5.95/6.09 (d, J= 12.0 Hz / bs, 1H),
7.17-7.40 (m, 4H), 7.57/7.72 (two dd, J= 1.6, 8.0 Hz / J= 2.0, 7.6 Hz, 1H). 13C NMR: δ= 37.3,
38.7, 52.4, 52.5, 64.8, 65.3, 67.1, 68.1, 126.4, 126.7, 127.2, 128.1, 128.4, 129.5, 129.7, 132.8,
133.5, 135.8, 140.0, 171.4, 171.9. HRMS (ESI): calcd for C11H12ClNO2S [M+H]+ 258.0350;
found [M+H]+ 258.0359.
(4R)-Methyl 2-(3-chlorophenyl)-1,3-thiazolidine-4-carboxylate (3e). The product was purified by
silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a pale
yellow oil. Yield: 81%. [α]ꢁꢀꢂ= -151.2 (c 1.03, CH2Cl2). IR (ATR, cm-1): 3308, 2951, 1735, 1595,
1571, 1434, 1226, 1200, 1176, 1158, 1076, 783, 693. 1H NMR (CDCl3): (mixture of
diastereoisomers) δ= 2.62/2.91 (two bs, 1H), 3.09-3.18 (m, 1H), 3.38/3.46 (two dd, J= 7.0, 10.6
Hz / J= 6.8, 10.4 Hz, 1H), 3.80/3.81 (two s, 3H), 3.96-4.00/4.11-4.15 (two m, 1H), 5.51/5.79 (two
s, 1H), 7.24-7.41 (m, 3H), 7.50-7.54 (m, 1H). 13C NMR: δ= 38.1, 39.2, 52.6, 52.7, 64.2, 65.5,
69.8, 71.7, 125.2, 125.8, 127.0, 127.7, 127.9, 128.9, 129.7, 130.0, 134.3, 134.6, 140.3, 143.8,
171.4, 172.1. HRMS (ESI): calcd for C11H12ClNO2S [M+H]+ 258.0350; found [M+H]+ 258.0356.
(4R)-Methyl 2-(4-chlorophenyl)-1,3-thiazolidine-4-carboxylate (3f). The product was purified by
silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a white
solid, after recrystallization from a mixture of diethyl ether and hexane. Yield: 78%. mp: 50-51
C. [α]ꢁꢀꢂ= -126.8 (c 1.03, CH2Cl2). IR (ATR, cm-1): 3306, 2952, 1735, 1488, 1434, 1202, 1157,
1088, 1013, 795, 729. 1H NMR (CDCl3): (mixture of diastereoisomers) δ= 3.11/3.17 (two dd, J=
9.1, 10.4 Hz / J= 6.0, 10.7 Hz, 1H), 3.38/3.46 (two dd, J= 7.0, 10.7 Hz / J= 7.1, 10.4 Hz, 1H),
3.79/3.81 (two s, 3H), 3.98/4.15 (dd, J= 7.1, 9.1 Hz / aprox. t, J= 6.6 Hz, 1H), 5.52/5.78 (two s,
1H), 7.27-7.35 (m, 2H), 7.41-7.48 (m, 2H). 13C NMR: δ= 38.1, 39.2, 52.7, 64.2, 65.5, 69.9, 71.8,
128.4, 128.5, 128.8, 128.9, 133.6, 134.5, 136.8, 140.0, 171.5, 172.1. HRMS (ESI): calcd for
C11H12ClNO2S [M+H]+ 258.0350; found [M+H]+ 258. 0356.
(4R)-Methyl 2-(2-methylphenyl)-1,3-thiazolidine-4-carboxylate (3g). The product was purified by
silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a pale
yellow oil. Yield: 68%. [α]ꢁꢀꢂ= -127.6 (c 0.98, CH2Cl2). IR (ATR, cm-1): 3309, 2951, 1735, 1457,
1
1433, 1319, 1268, 1198, 1157, 827, 754, 725. H NMR (CDCl3): (mixture of diastereoisomers)
δ= 2.41/2.43 (two s, 3H), 2.70 (bs, 1H), 3.11/3.22 (two dd, J= 9.0, 10.2 Hz / J= 5.8, 10.8 Hz,
1H), 3.41/3.47 (two dd, J= 7.0, 10.8 Hz / J= 7.0, 10.2 Hz, 1H), 3.81/3.81 (two s, 3H), 3.99/4.33

ACCEPTED MANUSCRIPT
(aprox. t, J= 8.0 Hz / dd, J= 5.8, 7.0 Hz, 1H), 5.76/5.95 (two s, 1H), 7.16-7.27 (m, 3H), 7.55-
7.57/7.66-7.68 (two m, 1H). 13C NMR: δ= 14.2, 19.4, 19.5, 21.0, 37.8, 39.1, 64.6, 65.5, 68.0,
69.3, 126.1, 126.2, 126.3 126.5, 127.7, 128.4, 130.5, 130.6, 135.8, 136.1, 136.5, 139.0, 171.7,
172.4. HRMS (ESI): calcd for C12H15NO2S [M+H]+ 238.0896; found [M+H]+ 238.0891.
(4R)-Methyl 2-(3-methylphenyl)-1,3-thiazolidine-4-carboxylate (3h). The product was purified by
silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a pale
yellow oil. Yield: 79%. [α]ꢁꢀꢂ= -120.0 (c 1.00, CH2Cl2). IR (ATR, cm-1): 3305, 2951, 1735, 1434,
1
1201, 1158, 827, 785, 759, 703. H NMR (CDCl3): (mixture of diastereoisomers) δ= 2.34/2.36
(two s, 3H), 2.71 (bs, 1H), 3.10/3.21 (two dd, J= 9.0, 10.4 Hz / J= 5.9, 10.6 Hz, 1H), 3.39/3.46
(two dd, J= 6.9, 10.6 Hz / J= 7.2, 10.4 Hz, 1H), 3.79/3.80 (two s, 3H), 3.98/4.23 (two dd, J= 7.2,
9.0 Hz / J= 5.9, 6.9 Hz, 1H), 5.53/5.78 (two s, 1H), 7.07-7.15 (m, 1H), 7.19-7.33 (m, 3H). 13C
NMR: δ= 21.4, 21.4, 38.1, 39.2, 52.6, 52.6, 64.4, 65.6, 70.9, 72.6, 124.0, 124.5, 127.6, 128.0,
128.4, 128.6, 128.7, 129.5, 138.1, 138.2, 138.5, 141.0, 171.6, 172.2. HRMS (ESI): calcd for
C12H15NO2S [M+H]+ 238.0896; found [M+H]+ 238.0891.
(4R)-Methyl 2-(4-methylphenyl)-1,3-thiazolidine-4-carboxylate (3i). The product was purified by
silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a brown oil.
Yield: 50%. [α]ꢁꢀꢂ= -97.4 (c 0.98, CH2Cl2). IR (ATR, cm-1): 3308, 2950, 1735, 1434, 1201, 1176,
1
1158, 809, 766. H NMR (CDCl3): (mixture of diastereoisomers) δ= 2.33/2.35 (two s, 3H),
2.65/2.76 (two bs, 1H), 3.10/3.21 (two dd, J= 9.0, 10.2 Hz / J= 5.8, 10.7 Hz, 1H), 3.38/3.45 (two
dd, J= 7.2, 10.7 Hz / J= 7.0, 10.2 Hz, 1H), 3.79/3.80 (two s, 3H), 3.97/4.23 (two aprox. t, J= 7.8
Hz / J= 6.4 Hz, 1H), 5.53/5.78 (two s, 1H), 7.13/7.17 (two d, J= 8.0 Hz / J= 8.2 Hz, 2H),
7.37/7.41 (two d, J= 8.0 Hz / J= 8.2 Hz, 2H). 13C NMR: δ= 21.1, 21.2, 38.1, 39.3, 45.4, 52.5,
52.6, 64.3, 65.5, 70.8, 72.5, 126.9, 127.3, 129.1, 129.4, 135.2, 137.7, 138.0, 138.6, 171.7,
172.3. HRMS (ESI): calcd for C12H15NO2S [M+H]+ 238.0896; found [M+H]+ 238.0890.
(4R)-Methyl 2-(1-naphthyl)-1,3-thiazolidine-4-carboxylate (3j). The product was purified by silica
gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a pale yellow
solid, after recrystallization from a mixture of diethyl ether and hexane. Yield: 46%. mp: 86-87
C. [α]ꢁꢀꢂ= -208.7 (c 1.03, CH2Cl2). IR (ATR, cm-1): 3285, 3050, 1731, 1434, 1266, 1219, 1170,
1
1158, 772, 745, 708. H NMR (CDCl3): (mixture of diastereoisomers) δ= 3.13/3.22 (two dd, J=
9.2, 10.1 Hz / J= 6.2, 10.5 Hz, 1H), 3.41/3.53 (two dd, J= 6.8, 10.5 Hz / J= 7.0, 10.1 Hz, 1H),
3.81/3.84 (two s, 3H), 4.11-4.16/4.37 (m / aprox. t, J= 6.6 Hz, 1H), 6.30/6.50 (two s, 1H), 7.41-
7.57 (m, 3H), 7.76-7.79 (m, 1H), 7.83-7.92 (m, 2H), 8.13/8.21 (two d, J= 8.4 Hz / J= 8.4 Hz, 1H).
13C NMR: δ= 37.9, 38.8, 52.6, 64.8, 65.6, 67.9, 69.5, 122.5, 123.6, 123.6, 123.8, 125.2, 125.3,
125.8, 125.9, 126.3, 126.5, 128.5, 128.7, 128.8, 129.2, 130.9, 131.4, 133.7, 133.7, 133.9,
136.7, 171.7, 172.4. HRMS (ESI): calcd for C15H15NO2S [M+H]+ 274.0896; found [M+H]+
274.0891.

ACCEPTED MANUSCRIPT
(4R)-Methyl 2-(2-naphthyl)-1,3-thiazolidine-4-carboxylate (3k). The product was purified by silica
gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give a white solid,
after recrystallization from a mixture of diethyl ether and hexane. Yield: 65%. mp: 89-90 C.
[α]ꢁꢀꢂ= -134.3 (c 1.01, CH2Cl2). IR (ATR, cm-1): 3335, 2946, 1726, 1448, 1434, 1217, 1191,
1
1137, 824, 801, 756. H NMR (CDCl3): (mixture of diastereoisomers) δ= 3.17/3.24 (two dd, J=
8.9, 10.2 Hz / J= 6.0, 10.6 Hz, 1H), 3.43/3.51 (two dd, J= 7.2, 10.6 Hz / J= 7.1, 10.2 Hz, 1H),
3.82/3.82 (two s, 3H), 4.05/4.27 (dd, J= 7.1, 8.9 Hz / aprox. t, J= 6.6 Hz, 1H), 5.74/6.00 (two s,
1H), 7.45-7.51 (m, 2H), 7.57/7.62 (two dd, J= 1.8, 8.6 Hz / J= 1.8, 8.6 Hz, 1H), 7.80-7.87 (m,
3H), 7.95-7.98 (m, 1H). 13C: δ= 38.2, 39.3, 52.6, 52.7, 64.4, 65.7, 70.9, 72.8, 125.0, 125.2,
125.4, 126.1, 126.3, 126.5, 126.6, 127.6, 127.7, 128.1, 128.4, 128.7, 133.0, 133.1, 133.1,
133.5, 135.4, 138.6, 171.6, 172.3. HRMS (ESI): calcd for C15H15NO2S [M+H]+ 274.0896; found
[M+H]+ 274.0898.
(4S)-Methyl 2-(3-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4b). The product
was purified by silica gel column chromatography using ethyl acetate:hexane (1:5) as eluent to
give a white solid. Yield: 83%. mp: 63-64 C. [α]ꢁꢀꢂ= +34.9 (c 2.01, CH2Cl2). IR (ATR, cm-1):
1
3330, 2952, 1739, 1609, 1585, 1455, 1440, 1265, 1155, 1121, 1043, 766, 755. H NMR
(CDCl3): (mixture of diastereoisomers) δ= 1.31/1.36 (two s, 3H), 1.62/1.72 (two s, 3H), 3.54 (bs,
1 H), 3.78-3.82 (m, 7H), 5.67/5.85 (two s, 1H), 6.77-6.79/6.86-6.87 (m/m, 1H), 7.07-7.12 (m,
2H), 7.21-7.30 (m, 1H). 13C NMR: δ= 26.1, 27.0, 27.4, 28.1, 51.1, 54.2, 54.3, 58.6, 59.0, 67.2,
69.0, 71.9, 73.7, 111.1, 111.8, 112.2, 113.0, 117.9, 118.7, 128.4, 128.7, 139.3, 143.8, 158.6,
158.8, 168.6, 169.2. HRMS (ESI): calcd for C14H19NO3S [M+H]+ 282.1158; found [M+H]+
282.1157.
(4S)-Methyl 2-(4-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4c). The product
was purified by silica gel column chromatography using as eluents first chloroform and then a
mixture of chloroform:methanol (10:1). A pale yellow oil was obtained. Yield: 83%. [α]ꢁꢀꢂ= +49.5
(c 1.01, CH2Cl2). IR (ATR, cm-1): 3319, 2957, 2926, 1735, 1609, 1509, 1456, 1433, 1244, 1204,
1172, 1156, 1125, 1030, 829, 766. 1H NMR (CDCl3): (mixture of diastereoisomers) δ= 1.31/1.36
(two s, 3H), 1.63/1.71 (two s, 3H), 3.40 (bs, 1H), 3.77-3.78 (m, 4H), 3.79/3.80 (two s, 3H),
5.65/5.84 (two s, 1H), 6.84-6.90 (m, 2H), 7.41-7.46 (m, 2H). 13C NMR: δ= 27.2, 28.4, 28.5, 29.2,
52.1, 52.1, 53.5, 55.3, 59.5, 59.9, 68.2 69.7, 72.8, 74.6, 113.7, 114.0, 127.9, 128.8, 130.6,
159.0, 159.8, 169.7, 170.3. HRMS (ESI): calcd for C14H19NO3S [M+H]+ 282.1158; found [M+H]+
282.1157.
(4S)-Methyl 2-(2-chlorophenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4d). The product
was purified by silica gel column chromatography using ethyl acetate:hexane (1:5) as eluent to
give a white solid. Yield: 74%. mp: 51-52 C. [α]ꢁꢀꢂ= +55.0 (c 1.00, CH2Cl2). IR (ATR, cm-1):
1
3330, 2953, 1740, 1609, 1585, 1455, 1438, 1264, 1201, 1155, 1121, 1043, 765, 755. H NMR
(CDCl3): (mixture of diastereoisomers) δ= 1.23/1.28 (two s, 3H), 1.51/1.65 (two s, 3H), 3.71/3.72

ACCEPTED MANUSCRIPT
(two s, 3H), 3.74/3.85 (two s, 1H), 5.97/6.01 (two s, 1H), 7.07-7.30 (m, 3H), 7.58/7.68 (two dd,
J= 1.6, 8.0 Hz / J= 1.6, 7.6 Hz, 1H). 13C NMR: δ= 26.0, 26.2, 27.4, 27.9, 51.1, 51.2, 57.8, 58.3,
64.2, 64.7, 72.3, 73.5, 125.2, 125.9, 126.3, 127.2, 127.3, 128.6, 128.6, 128.7, 131.6, 132.8,
135.2, 140.1, 168.6, 168.9. HRMS (ESI): calcd for C13H16ClNO2S [M+H]+ 286.0663; found
[M+H]+ 286.0651.
(4S)-Methyl 2-(3-chlorophenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4e). The product
was purified by silica gel column chromatography using ethyl acetate:hexane (1:6) as eluent to
give a pale yellow oil. Yield: 96%. [α]ꢀꢁꢂ= +100.0 (c 1.00, CH2Cl2). IR (ATR, cm-1): 3309, 2958,
1
2925, 1735, 1433, 1311, 1203, 1128, 868, 849, 771, 693. H NMR (CDCl3): (mixture of
diastereoisomers) δ= 1.30/1.36 (two s, 3H), 1.61/1.72 (two s, 3H), 3.74/3.78 (two s, 1H),
3.79/3.79 (two s, 3H), 5.64/5.81 (two s, 1H), 7.21-7.41 (m, 3H), 7.50-7.53 (m, 1H). 13C NMR: δ=
27.1, 27.9, 28.4, 29.1, 52.2, 52.3, 59.7, 60.4, 67.4, 69.0, 72.7, 74.5, 124.9, 125.9, 126.6, 127.5,
127.8, 128.9, 129.6, 130.0, 134.3, 134.6, 140.5, 140.6, 169.5, 170.0. HRMS (ESI): calcd for
C13H16ClNO2S [M+H]+ 286.0663; found [M+H]+ 286.0664.
(4S)-Methyl 2-(4-chlorophenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4f). The product was
purified by silica gel column chromatography using ethyl acetate:hexane (1:6) as eluent to give
a white solid, after recrystallization from diethyl ether. mp: 150-152 C. Yield: 82%. [α]ꢁꢀꢂ=
+10.0 (c 2.00, CH2Cl2). IR (ATR, cm-1): 3321, 2957, 1735, 1488, 1433, 1312, 1204, 1122, 1088,
1
1013, 827, 779, 761. H NMR (CDCl3): (mixture of diastereoisomers) δ= 1.30/1.35 (two s, 3H),
1.61/1.72 (two s, 3H), 3.72-3.79 (m, 4H), 5.65/5.81 (two s, 1H), 7.27-7.35 (m, 2H), 7.41-7.47 (m,
2H). 13C NMR: δ= 27.2, 28.1, 28.4, 29.1, 52.2, 59.9, 60.3, 67.5, 69.3, 72.8, 74.7, 128.0, 128.4,
128.8, 129.0, 133.1, 134.4, 137.3, 141.7, 169.6, 170.1. HRMS (ESI): calcd for C13H16ClNO2S
[M+H]+ 286.0663; found [M+H]+ 286.0664.
(4S)-Methyl 2-(2-methylphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4g). The product
was purified by silica gel column chromatography using ethyl acetate:hexane (1:6) as eluent to
give a white solid, after recrystallization from a mixture of diethyl ether and hexane. Yield: 83%.
mp: 65-66 C. [α]ꢁꢀꢂ= +28.7 (c 2.97, CH2Cl2). IR (ATR, cm-1): 3322, 2957, 1730, 1457, 1431,
1
1317, 1205, 1118, 761. H NMR (CDCl3): (mixture of diastereoisomers) δ= 1.26/1.29 (two s,
3H), 1.55/1.66 (two s, 3H), 2.26/2.34 (two s, 3H), 3.71/3.72 (two s, 3H), 3.72/3.87 (two s, 1H),
5.84/5.92 (two s, 1H), 7.05-7.20 (m, 3H), 7.56-7.58/7.64 (m / dd, J=1.2, 7.6 Hz, 1H). 13C NMR:
δ= 19.4, 19.7, 27.3, 27.6, 28.6, 29.2, 52.2, 59.3, 59.4, 65.8, 66.6, 73.4, 74.8, 124.9, 126.2,
126.4, 126.4, 126.6, 127.4, 128.3, 128.4, 130.6, 130.7, 135.2, 136.6, 136.7, 141.2, 169.9,
170.4. HRMS (ESI): calcd for C14H19NO2S [M+H]+ 266.1209; found [M+H]+ 266.1204.
(4S)-Methyl 2-(3-methylphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4h). The product
was purified by silica gel column chromatography using ethyl acetate:hexane (1:6) as eluent to
give a viscous pale yellow oil. Yield: 83%. [α]ꢁꢀꢂ= +45.0 (c 1.00, CH2Cl2). IR (ATR, cm-1): 3327,

ACCEPTED MANUSCRIPT
2953, 2922, 1736, 1453, 1432, 1313, 1251, 1202, 1156, 1126, 851, 767, 687. 1H NMR (CDCl3):
(mixture of diastereoisomers) δ= 1.32/1.36 (two s, 3H), 1.63/1.72 (two s, 3H), 2.34/2.36 (two s,
3H), 3.17 (bs, 1H), 3.78/3.79/3.80 (two s / bs, 4H), 5.66/5.85 (two s, 1H), 7.05/7.13 (two d, J=
7.2 Hz / J= 7.2 Hz, 1H), 7.18-7.31 (m, 3H). 13C NMR: δ= 21.4, 21.5, 27.2, 28.0, 28.5, 29.2, 52.1,
59.7, 60.0, 68.3, 70.2, 73.0, 74.8, 123.6, 124.5, 127.1, 128.1, 128.2, 128.3, 128.6, 129.4, 138.1,
138.4, 138.6, 143.0, 169.8, 170.3. HRMS (ESI): calcd for C14H19NO2S [M+H]+ 266.1209; found
[M+H]+ 266.1207.
(4S)-Methyl 2-(4-methylphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4i). The product
was purified by silica gel column chromatography using ethyl acetate:hexane (1:6) as eluent to
give a brown solid, after recrystallization from a mixture of diethyl ether and hexane. Yield: 71%.
mp: 57-59 C. [α]ꢁꢀꢂ= +63.1 (c 1.98, CH2Cl2). IR (ATR, cm-1): 2955, 2923, 1741, 1608, 1508,
1
1433, 1205, 1178, 1155, 1120, 772, 759. H NMR (CDCl3): (mixture of diastereoisomers) δ=
1.31/1.35 (two s, 3H), 1.62/1.72 (two s, 3H), 2.32/2.35 (two s, 3H), 3.15 (t, J= 11.2 Hz, 1H),
3.76/3.78/3.78 (bs / two s, 4H), 5.67/5.85 (d, J= 10.4 Hz / s, 1H), 7.13/7.17 (two d, J= 8.0 Hz /
J= 7.6 Hz, 2H), 7.37/7.40 (two d, J= 8.0 Hz / J= 8.0 Hz, 2H). 13C NMR: δ= 21.1, 21.2, 27.2, 28.2,
28.5, 29.2, 52.1, 52.1, 59.6, 59.9, 68.3, 70.0, 72.9, 74.8, 126.5, 127.4, 129.0, 129.3, 135.7,
137.1, 138.5, 140.1, 169.8, 170.3. HRMS (ESI): calcd for C14H19NO2S [M+H]+ 266.1209; found
[M+H]+ 266.1210.
(4S)-Methyl 2-(1-naphthyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4j). The product was
purified by silica gel column chromatography using ethyl acetate:hexane (1:3) as eluent to give
a pale yellow oil. Yield: 41%. [α]ꢁꢀꢂ= +190.2 (c 1.03, CH2Cl2). IR (ATR, cm-1): 3325, 3050, 2955,
2922, 1735, 1453, 1431, 1203, 1128, 851, 774. 1H NMR (CDCl3): (mixture of diastereoisomers)
δ= 1.35/1.37 (two s, 3H), 1.58/1.77 (two s, 3H), 3.35 (bs, 1H), 3.78/3.80 (two s, 3H), 3.94/4.02
(d, J= 9.6 Hz / s, 1H), 6.45/6.49 (d, J= 8.4 Hz / s, 1H), 7.42-7.55 (m, 3H), 7.72-8.21 (m, 4H). 13
C
NMR: δ= 27.2, 27.3, 28.4, 29.1, 52.2, 59.0, 59.0, 65.4, 66.5, 73.4, 74.9, 121.6, 123.4, 123.7,
123.7, 125.4, 125.4, 125.7, 125.9, 126.1, 126.5, 128.0, 128.7, 128.9, 129.0, 130.4, 131.5,
133.7, 134.1, 134.5, 138.7, 169.8, 170.3. HRMS (ESI): calcd for C17H19NO2S [M+H]+ 302.1209;
found [M+H]+ 302.1208.
(4S)-Methyl 2-(2-naphthyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate (4k). The product was
purified by silica gel column chromatography using ethyl acetate:hexane (1:6) as eluent to give
a white solid, after recrystallization from a mixture of diethyl ether and hexane. Yield: 80%. mp:
87-89 C. [α]ꢁꢀꢂ= +57.8 (c 1.99, CH2Cl2). Elemental analysis: C17H19NO2S calcd C, 67.74; H,
6.35; N, 4.65; S, 10.64. Found: C, 67.99; H, 5.89; N, 4.56; S, 10.54. IR (ATR, cm-1): 3333, 2955,
1
2928, 1735, 1431, 1345, 1300, 1267, 1223, 1199, 1183, 1153, 1130, 1121, 826, 753. H NMR
(CDCl3): (mixture of diastereoisomers) δ= 1.34/1.41 (two s, 3H), 1.63/1.76 (two s, 3H), 3.31 (bs,
1H), 3.80/3.80 (two s, 3H), 3.84/3.85 (two bs, 1H), 5.86/6.03 (two s, 1H), 7.44-7.51 (m, 2H),
7.53/7.62 (two dd, J= 1.8, 8.6 Hz / J= 2.0, 8.4 Hz, 1H), 7.78-7.87 (m, 3H), 7.96/7.97 (two bs,

ACCEPTED MANUSCRIPT
1H). 13C NMR: δ= 27.3, 28.1, 28.5, 29.2, 52.2, 59.8, 60.2, 68.5, 70.3, 72.9, 74.8, 124.6, 125.1,
125.2, 125.9, 126.2, 126.4, 126.6, 127.6, 127.7, 128.1, 128.1, 128.3, 128.6, 132.9, 133.1,
133.4, 135.9, 140.3, 169.7, 170.3.
General procedure for enantioselective ethylation reaction
To the chiral ligand (0.15 mmol) and aldehyde (1 mmol) in an inert atmosphere, dry solvent (4
mL) was added. The temperature of the reaction mixture was lowered to 0 C and diethylzinc
(2 mmol, 2 mL, as a 1 M hexane solution) was added. The reaction was stirred for 10 min at 0
C and then for the required time at room temperature. Subsequently, a saturated NH4Cl
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 conversions and ee of the products.[43]
Results and Discussion
Ligand Synthesis
Our interest was focused on the synthesis of thiazolidines 3 and 4, Scheme 1, bearing phenyl
groups at C2, with electron donating and electron withdrawing groups in various positions, and
also 1- and 2-naphthyl groups. In order to synthesize these compounds, the methyl esters of
cysteine, 1, and -penicillamine, 2 were used as precursors.
L-
D
Scheme 1 L-cysteine, 1, and D-penicillamine, 2, derived thiazolidines 3 and 4, respectively.
Starting from commercially available 1, thiazolidines 3 were obtained by reaction with a
series of aromatic aldehydes in ethanol/water at room temperature.[44] In order to obtain
thiazolidines 4,
D-penicillamine was esterified with thionyl chloride in refluxing methanol to
originate 2.[45] After several attempts at optimizing this reaction, it was found that,
independently of the reaction time, the product always contained about 25% of the free acid.
With this mixture, without further purification, thiazolidines 4 were prepared using the above
described procedure for the synthesis of 3. Although the
L-cysteine derivatives were formed with
good yields following this procedure, we observed that the
D-penicillamine thiazolidines only

ACCEPTED MANUSCRIPT
gave moderate yields after long reaction times. In an attempt to improve the yields and reduce
the reaction times, the condensation was performed in refluxing cyclohexane[46], but still very
long reaction times were required for good yields (up to 72 hours).
Given the good results previously observed by us using microwave irradiation in the
synthesis of imines,[24] the effects of applying this technology to the synthesis of the above-
mentioned compounds was explored. In order to optimize reaction conditions, the synthesis of
thiazolidine 4c from 2 and p-anisaldehyde, in the presence of triethylamine, and using water as
solvent, was used as model, Table 1. Best results were obtained using microwave irradiation for
15 min at 100 C (83%). The resulting high yields, along with a large reduction of the reaction
time and the possibility of using water, thus reducing the use of more harmful and polluting
organic solvents, make this an efficient and simple method for synthesizing thiazolidines. Using
these conditions, a series of C2 aromatic thiazolidines, 3a-k and 4a-k, were obtained with
moderate to excellent yields, Scheme 2, Table 2. The thiazolidines are formed as C2
diastereoisomeric mixtures, which can interconvert in solution, through opening and closing of
the thiazolidine ring.[47–49]
Table 1 Optimization of the synthesis of 4c under microwave irradiation.
Entry
Temperature
( C)
100
Time
Yield
(%)a
(minutes)
1
2
15
30
60
15
30
60
120
90
30
30
82
100
76
3
100
77
4
120
75
5
120
70
6
120
76
7
120
74
8
110
decomposition
decomposition
decomposition
9
120
10
150
aDetermined by 1H NMR
Scheme 2 Synthesis of L-cysteine and D-penicillamine derived thiazolidines.

ACCEPTED MANUSCRIPT
Table 2 Thiazolidines derived from L-cysteine and D-penicillamine.
Ligand
3a
3b
3c
3d
3e
3f
R
H
H
H
H
H
H
H
H
H
H
H
Ar
Yield (%)
(o-OCH3)C6H4 85
(m-OCH3)C6H4 71
(p-OCH3)C6H4 68
(o-Cl)C6H4
(m-Cl)C6H4
(p-Cl)C6H4
(o-CH3)C6H4
(m-CH3)C6H4
(p-CH3)C6H4
1-naphthyl
2-naphthyl
71
81
78
68
79
50
46
65
3g
3h
3i
3j
3k
4a
4b
4c
4d
4e
4f
CH3 (o-OCH3)C6H4 83
CH3 (m-OCH3)C6H4 83
CH3 (p-OCH3)C6H4 83
CH3 (o-Cl)C6H4
CH3 (m-Cl)C6H4
CH3 (p-Cl)C6H4
CH3 (o-CH3)C6H4
CH3 (m-CH3)C6H4
CH3 (p-CH3)C6H4
CH3 1-naphthyl
CH3 2-naphthyl
74
96
82
83
83
71
41
80
4g
4h
4i
4j
4k
Enantioselective Ethylation of Aldehydes
Thiazolidines 3 and 4 were tested as ligands in the enantioselective ethylation of aldehydes with
diethylzinc, using our previously described conditions, Scheme 3.[43] The results of the
ethylation of benzaldehyde using diethylzinc, performed at room temperature, in cyclohexane,
with 15 mol% of 3 and 4 are summarized in Table 3.

ACCEPTED MANUSCRIPT
Scheme 3 Enantioselective alkylation of benzaldehyde with 3a-3k and 4a-4k.
Table 3 Enantioselective ethylation of benzaldehyde catalyzed by chiral thiazolidines 3-4a.
Ligand Conversion (%)b 1-Phenylpropan-1-ol (%)b,c ee (%)d
3a
3b
3c
3d
3e
3f
91
92
95
81
83
77
98
95
98
92
96
86
97
99
>99
98
99
98
99
98
98
99
98
98
57 (S)
70 (S)
61 (S)
74 (S)
63 (S)
70 (S)
69 (S)
69 (S)
66 (S)
77 (S)
70 (S)
84 (R)
89 (R)
83 (R)
83 (R)
77 (R)
83 (R)
86 (R)
82 (R)
85 (R)
88 (R)
81 (R)
93
89
>99
98
3g
3h
3i
>99
98
99
3j
98
3k
4a
4b
4c
4d
4e
4f
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
4g
4h
4i
4j
4k
aReaction conditions: cyclohexane (4 mL), ligand (15 mol%), benzaldehyde (1
mmol), diethylzinc solution 1 M in hexane (2 mmol), rt, 24 h. bDetermined by GC.
d
cRelative to converted benzaldehyde. Determined by GC on a chiral column. The
major enantiomer is indicated in parenthesis.
The use of ligands 3 and 4 allowed an efficient alkylation of benzaldehyde, with
conversions above 89%. In general, higher conversions were observed with the
D-penicillamine
thiazolidines, 4, giving chiral products with good ee (77-89%). The -cysteine thiazolidines, 3,
L

ACCEPTED MANUSCRIPT
gave moderate ee (57-77%). The two methyl groups in C5, creating significant steric hindrance,
appear to be responsible for these results. Moreover, the opposite absolute configuration at C4
of
of the product alcohols.
The electron-donating and electron-withdrawing nature of the substituents in the
L-cysteine and D-penicillamine thiazolidines makes it possible to obtain the two enantiomers
aromatic ring at C2, as well as their location in ortho, meta, or para positions, does not appear
to significantly affect the enantioselectivity. However, it is possible to observe that the electron-
donating methoxy substituent in meta in ligands 3b and 4b increases the chiral induction (70%
and 89%, respectively), when compared to their ortho and para analogues. The opposite is
verified for the electron-withdrawing chloride group, with ligands 3e and 4e originating lower ee
(63% and 77%, respectively) when in the meta position.
Comparing the thiazolidines with 1-naphthyl (3j, 4j) and 2-naphthyl (3k, 4k) substituents
at C2, the former gave 1-phenylpropan-1-ol with higher ee.
In order to determine the effect of temperature on reactivity and selectivity, some
reactions were conducted at 0 C. As expected, the conversions were lower in almost all
cases, with no noteworthy differences in ee.
In an attempt to improve the results, different solvents and catalyst loadings were
tested, using our most promising ligand, 4b, Table 4. Better conversions and ee were obtained
with non-polar solvents, although cyclohexane remained the best. The use of different catalyst
loadings did not affect the conversion of benzaldehyde, the best enantioselectivity being
observed with 15 mol% of 4b.
Table 4 Enantioselective alkylation of benzaldehyde with 4b, with different solvents and catalyst loadings.
Solvent
Cyclohexane
Hexane
4b (mol%) Conversion (%)b1-Phenylpropan-1-ol (%)b,c ee (%)d
15
15
15
15
15
10
20
>99
>99
96
>99
98
89 (R)
85 (R)
87 (R)
88 (R)
77 (R)
86 (R)
86 (R)
Toluene
93
Diethyl ether
Dichloromethane
Cyclohexane
Cyclohexane
93
95
74
87
>99
>99
98
>99
aReaction conditions: solvent (4 mL), 4b (15 mol%), benzaldehyde (1 mmol), diethylzinc solution 1 M in hexane
b
c
d
(2 mmol), rt, 24 h. Determined by GC. Relative to converted benzaldehyde. Determined by GC on a chiral
column. The major enantiomer is indicated in parenthesis.
The possibility of reducing the reaction time was also studied. Aliquots of the catalytic
mixture were taken at 2h intervals and analyzed. It was observed that after 6 hours no
significant changes occurred. Thus, under our newly optimized conditions, 6 h reaction in
cyclohexane, with 15 mol% of 4b at room temperature, we examined the scope of our ligand by
testing a series of substrates, Table 5. Very good to excellent conversions were observed with
all of the aromatic substrates, with the best ee being obtained with m- and p-
methoxybenzaldehyde (93% ee). The methoxy group in the ortho position could cause steric

ACCEPTED MANUSCRIPT
hindrance responsible for a slight decrease in ee. The increasing distance of the electron-
withdrawing chlorine atom to the carbonyl group results in lower conversions and slightly lower
ee. Very good ee were obtained with bulkier aldehydes such as 1- and 2-naphthaldehyde (94%
and 87%, respectively), although conversions were moderate. While aliphatic
phenylacetaldehyde
gave
poor
conversion
and
ee,
cinnamaldehyde,
cyclohexanecarboxaldehyde and the heteroaromatic furfuraldehyde were converted efficiently
to the chiral alcohols (>95% conversion), with moderate to good ee. Overall, these results
highlight the efficiency of this catalytic system.
Table 5 Enantioselective alkylation of several aldehydes catalyzed by 4b.
Aldehyde
Conversion (%)b ee (%)c
o-Methoxybenzaldehyde
m-Methoxybenzaldehyde
p-Methoxybenzaldehyde
o-Chlorobenzaldehyde
m-Chlorobenzaldehyde
p-Chlorobenzaldehyde
m-Methylbenzaldehyde
1-Naphthaldehyde
97
97
84 (R)
93 (R)
93 (R)
81 (R)
80 (R)
78 (R)
78 (R)
94 (R)
87 (R)
50 (R)
77 (R)
72 (R)
58
>99
>99
95
90
89
61
2-Naphthaldehyde
83
Furfuraldehyde
>99
95
Cinnamaldehyde
Cyclohexanecarboxaldehyde
>99
Phenylacetaldehyde
27
aReaction conditions: cyclohexane (4 mL), 5b (15 mol%), aldehyde (1
mmol), diethylzinc solution 1 M in hexane (2 mmol), rt, 6 h reaction.
Determined by GC. cDetermined by GC on a chiral column. The major
enantiomer is indicated in parenthesis.
NMR and Computational Studies of the Relative Stability of Diastereoisomers
and Catalytically Active Species
NMR Studies
In order to get an insight into the mechanism of the enantioselective ethylation reactions with
diastereoisomeric mixtures of thiazolidines, as well as to try to identify the active species in the
catalytic cycle, NMR and computational studies were performed, using the most
enantioselective ligand, 4b.
In successive recrystallizations of 4b, we were able to isolate only one of the two
diastereoisomers as a crystalline white solid. Using this compound, the evolution of the
diastereoisomeric equilibrium in solution by 1H NMR was studied, collecting spectra 0, 1 and 5
hours after dissolution, as well as after 1 and 5 days (see Supporting Information). The singlets

ACCEPTED MANUSCRIPT
of the hydrogen of carbon 2 of the thiazolidine (δ= 5.67/5.85 ppm) were used to calculate the
ratio of the diastereoisomers, Table 6. Taking these results into account, it is possible to confirm
that, in solution, interconversion of the two diastereoisomers occurs, reaching an equilibrium in
a proportion of 1:3. This epimerization arises from the ring opening and closing of the
thiazolidine, with formation of an imine intermediate, Scheme 4, 4b-2, that could not be
observed by NMR.
Table 6 Variation of the diastereoisomeric ratio with time.
Time after dissolution Diastereoisomeric Ratio (minor:major)
0 hour
1 hour
5 hours
1 day
0:1
1:26
1:12
1:4
5 days
1:3
Scheme 4 Epimerization of thiazolidine 4b via intermediate imine formation.
In order to try to identify the most stable diastereoisomer, 2D-NOESY spectra were
recorded instantaneously after dissolution of the sample and 5 days later (see Supporting
Information for spectra). From the signals of the hydrogen of carbon 2, it is possible to observe,
for the major diastereoisomer, a space interaction with the hydrogen of carbon 4 (δ around 3.78
ppm), in both NOESY spectra. However, there was no evidence of this interaction for the minor
diastereoisomer. The spatial proximity of these hydrogens when in cis position could be
responsible for this interaction, which allowed to identify the cis diastereoisomer 4b-1 as the
major and most stable one.
This NMR study confirms that there is no need to obtain the thiazolidines in a pure
diastereoisomeric form, since they will immediately epimerize when dissolved in the catalytic
reaction solvent. However, the question still prevails: can the use of thiazolidine ligands as
diastereoisomeric mixtures affect enantioselective induction? In literature, it has been referred
that the selectivity is not affected, which could result from distinct characteristics of the two

ACCEPTED MANUSCRIPT
possible diastereoisomeric catalysts, namely, significantly different rates of reaction or lack of
coordination of one of the diastereoisomers, with the other forming the active catalyst.[34,50,51]
In order to try to answer this question, the enantioselective ethylation of benzaldehyde using 4b
in its pure diastereoisomeric form was carried out. After 6 hours complete conversion of the
substrate was observed and (R)-1-phenylpropan-1-ol was obtained with an ee of 86%, which
matches the 85% ee achieved with the use of thiazolidine 4b as a mixture of diastereoisomers.
Thereby, in the case of thiazolidine ligands, the catalytic reaction is not compromised by the use
of diastereoisomeric mixtures of ligands.
Computational Studies
In order to determine the stability of the two diastereoisomers and to rationalize the
differences in catalytic activity of each one, first-principles calculations were performed, using
the Orca electronic structure package (version 4.0.0).[52] For each of the diastereoisomers, the
structures of the free ligand and of those resulting from the complexation with one and two zinc
atoms (according to Noyori’s mechanism of the alkylation reaction[4,53]) were optimized at the
hybrid DFT level, using the PBE0 functional with the 6-31G(d) polarized double-ζ basis set.[54]
The schematic representation of these structures is presented in Fig. 1.
The optimized geometries are shown in Fig. 2 and their respective energies presented
in Table 7. Single point energy calculations for each optimized species were also performed
using the PBE0 functional with the cc-pVDZ, cc-pVTZ and cc-pVQZ series of Dunning’s
correlation-consistent basis sets, Table 7.[55–57] The data thus obtained indicates that the
energies calculated with the cc-pVnZ basis sets are already well converged with n = T. Although
the smaller 6-31G(d) basis set does predict the correct order of stability the energies obtained at
this level are clearly inferior to those from the correlation-consistent basis sets and should not
be relied upon for quantitative work on ligands/complexes of this type. The graphics that
correspond to the energy differences for equivalent species are presented in Fig. 3 to 5.

ACCEPTED MANUSCRIPT
O
OCH3
OCH3
OCH3
O
O
S
N
Zn
S
N
Zn
O
NH
S
CH2
Zn
cis species
OCH3
4bB
OCH3
4bC
OCH3
4bA
OCH3
O
OCH3
OCH3
O
O
S
N
Zn
O
S
N
Zn
NH
S
CH2
Zn
trans species
OCH3
4bF
OCH3
OCH3
4bD
4bE
Fig. 1 Schematic representation of the free and complexed cis and trans structures.
Fig. 2 Optimized geometries of the intended species at the DFT level, using PBE0/6-31G(d) level of theory. Color code:
grey, carbon; red, oxygen; blue, nitrogen; white, hydrogen; yellow, sulphur; and blue-grey, zinc.

ACCEPTED MANUSCRIPT
Table 7 Energy values for the optimization structure and single point energy calculations at the PBE0 level of theory.
Energy (KJ/mol)
6-31G(d)
4bA -3209496,5
4bD -3209493,3
4bB -8086052,6
4bE -8086003,1
cc-pVDZ
-3209729,4
-3209726,9
-8087212,9
-8087168,4
cc-pVTZ
-3210352,3
-3210348,5
-8087893,5
-8087849,4
cc-pVQZ
-3210523,3
-3210519,1
-8088085,9
-8088041,6
4bC -13472060,9 -13474182,6 -13475074,3 -13475325,4
4bF -13472105,8 -13474227,8 -13475115,1 -13475365,5
Fig. 3 Graphical representation of the energy difference between species 4bA and 4bD.

ACCEPTED MANUSCRIPT
Fig. 4 Graphical representation of the energy difference between species 4bB and 4bE.
Fig. 5 Graphical representation of the energy difference between species 4bC and 4bF.
From the obtained results the species generated from each one of the diastereoisomers
can be compared. For the free ligand (4bA and 4bD), the cis diastereoisomer is the most stable
one, since it is associated with more negative energy values. The energy difference around 4
KJ/mol allows us to postulate that, besides the higher stability of the cis isomer, an
interconversion to the trans isomer can occur (assuming thermodynamic equilibrium between
diastereoisomers). This result is in agreement with the one obtained experimentally from the
NMR studies. Looking at the species containing one zinc (4bB and 4bE), it is possible to
observe that the more stable complex is obtained with the cis diastereoisomer, which seems to
coordinate preferentially with the zinc atom. However, moving along the reaction path, a
coordination with a second diethylzinc molecule occurs. This second complexation is
determinant for the reaction, since it allows the transfer of the ethyl group to the carbonyl group
of the aldehyde and, therefore, the definition of the stereochemistry of the product. From the
computational studies, it was possible to observe that the species resulting from the
complexation of the trans diastereoisomer with the second zinc atom (4bF) is more stable than
the one derived from the cis thiazolidine (4bC), with an energy difference of about 40 KJ/mol.
This can be explained by a more sterically hindered environment in the cis structure, resulting in
a preferential course of the reaction through the trans structure, this being the most catalytically
active species (although both can intervene in the reaction).

ACCEPTED MANUSCRIPT
Conclusions
A new series of chiral 2-arylthiazolidines derived from L-cysteine and D-penicillamine were
synthesized. A new, simple and greener procedure was developed, taking advantage of
microwave irradiation, which allowed the formation of the desired thiazolidines with good yields
in only 15 minutes.
The new thiazolidines were tested as ligands in the enantioselective ethylation of
benzaldehyde, providing good to excellent conversions and ee up to 89%. The
derived thiazolidines proved to be more efficient chiral inducers, giving (R)-1-phenylpropan-1-ol
with higher ee than the -cysteine based ligands, which originated (S)-1-phenylpropan-1-ol. The
D-penicillamine
L
use of precursors with opposite chirality, does, however, create an interesting and useful
strategy for the synthesis of both enantiomers of the chiral products. The results seem to
indicate that the nature and position of the substituents on the C2 aromatic group are not the
determining factors in obtaining good ee. Nevertheless, they do influence the enantioselectivity.
Using the optimized reaction parameters, the most selective ligand, 4b, was used to
evaluate the scope of the reaction. Aromatic substrates, provided good conversions and ee up
to 94%. Heteroaromatic and aliphatic aldehydes were also studied, giving ee up to 77%, an
interesting value for this kind of substrates.
NMR studies with ligand 4b confirmed that epimerization occurs with this kind of ligands
in solution. The cis diastereoisomer of 4b was identified as the most stable one and the major
isomer present at equilibrium in a 3:1 ratio. The use of ligand 4b in pure diastereoisomeric form
in the catalytic process led to the same results as the mixture of cis and trans isomers, thus
endorsing the use of the mixture. Computational calculations were in agreement with the
experimental results, confirming the cis diastereoisomer (4bA) as the most stable and the
possibility of its interconversion to the trans diastereoisomer (4bD). The species resulting from
coordination with a second diethylzinc molecule proved to invert this order of stability, the trans
thiazolidine forming a more stable catalyst (4bF). This favored structure seems to be the main
species responsible for the catalytic process, possibly due to a less hindered environment in the
neighborhood of the zinc atoms.
Studies are underway aiming at the synthesis of thiazolidines with other functionalities
and their subsequent evaluation in new enantioselective transformations.
Conflicts of Interest
There are no conflicts to declare.
Acknowledgements and Funding Sources
Thanks are due to Coimbra Chemistry Centre (CQC), supported by the Portuguese Agency for
Scientific Research, Fundação para a Ciência e a Tecnologia (FCT) through Project Nº 007630

ACCEPTED MANUSCRIPT
UID/QUI/00313/2013, co-funded by COMPETE2020-UE. Nélia C. T. Tavares and Bruce F.
Milne also thank FCT for funding (PhD grant PD/BD/128496/2017 and project CENTRO-01-
0145-FEDER-000014, 2017—2020, respectively). We thank Prof. Fernando Nogueira and the
Laboratory for Advanced Computing (LCA) of the University of Coimbra for technical support
and computer time allocated to this project. We also acknowledge the UC-NMR facility for
obtaining the NMR data (www.nmrccc.uc.pt).
References
[1] T. Mukaiyama, K. Soai, S. Kobayashi, Enantioface-differentiating (asymmetric) addition of
alkyllithium to aldehydes by using (2S, 2’S)-2-hydroxymethyl-1-[(1-methylpyrrolidin-2-
yl)methyl]-
pyrrolidine
as
chiral
ligand,
Chem.
Lett.
(1978)
219–222.
doi:10.1017/CBO9781107415324.004.
[2] N. Oguni, T. Omi, Enantioselective addition of diethylzinc to benzaldehyde catalyzed by a
small amount of chiral 2-amino-1-alcohols, Tetrahedron Lett. 25 (1984) 2823–2824.
doi:10.1017/CBO9781107415324.004.
[3] M. Kitamura, S. Suga, K. Kawai, R. Noyori, Catalytic asymmetric induction. Highly
enantioselective addition of dialkylzincs to aldehydes, J. Am. Chem. Soc. 108 (1986)
6072–6074. doi:10.1021/ja00257a034.
[4] M. Yamakawa, R. Noyori, An ab initio molecular orbital study on the amino alcohol-
promoted reaction of dialkylzincs and aldehydes, J. Am. Chem. Soc. 117 (1995) 6327–
6335. doi:10.1021/ja00128a023.
[5] G.Q. Lin, Y.M. Li, A.S.C. Chan, A.J. Wiley, Principles and Applications of Asymmetric
Synthesis, John Wiley & Sons, Inc., New York, 2001.
[6] C.M. Binder, B. Singaram, Asymmetric addition of diorganozinc reagents to aldehydes and
ketones, Org. Prep. Proced. Int. 43 (2011) 139–208. doi:10.1080/00304948.2011.564538.
[7] D. Łowicki, S. Bas, J. Mlynarski, Chiral zinc catalysts for asymmetric synthesis,
̈
Tetrahedron. 71 (2015) 1339–1394. doi:10.1016/j.tet.2014.12.022.
[8] K. Soai, S. Nlwa, Enantioselective addition of organozinc reagents to aldehydes, Chem.
Rev. 92 (1992) 833–856. doi:10.1021/cr00013a004.
[9] C. Wolf, C.J. Francis, P.A. Hawes, M. Shah, Enantioselective alkylation of aldehydes
promoted by (S)-tyrosine-derived β-amino alcohols, Tetrahedron Asymmetry. 13 (2002)
1733–1741. doi:10.1016/S0957-4166(02)00469-X.
[10] M.I. Burguete, J. Escorihuela, S. V. Luis, A. Lledóss, G. Ujaque, New chiral tetraaza
ligands for the efficient enantioselective addition of dialkylzinc to aromatic aldehydes,
Tetrahedron. 64 (2008) 9717–9724. doi:10.1016/j.tet.2008.07.099.
[11] T.D.L.C. Engel, B.L. Maroto, S.D.L.M. Cerero, Ketopinic acid derived bis(hydroxy amides)
as cheap, chiral ligands for the enantioselective ethylation of aromatic aldehydes,
European J. Org. Chem. (2010) 1717–1727. doi:10.1002/ejoc.200901391.

ACCEPTED MANUSCRIPT
[12] S. Gou, Z. Ye, G. Gou, M. Feng, J. Chang, Modular amino acids and β-amino alcohol-
based chiral ligands for enantioselective addition of diethylzinc to aromatic aldehydes,
Appl. Organomet. Chem. 25 (2011) 110–116. doi:10.1002/aoc.1724.
[13] S.Y. Kang, Y.S. Park, Discovery of dipeptide-derived catalysts for the enantioselective
addition of dimethylzinc to aldehydes, European J. Org. Chem. (2012) 1703–1706.
doi:10.1002/ejoc.201200063.
[14] K. Michigami, M. Hayashi, Enantioselective alkylation of aldehydes using dialkylzincs
catalyzed by simple chiral diols derived from naturally occurring monosaccharides,
Tetrahedron. 69 (2013) 4221–4225. doi:10.1016/j.tet.2013.03.090.
[15] Y. Naganawa, T. Namba, T. Aoyama, K. Shoji, H. Nishiyama, Design of novel chiral N,N,O-
tridentate phenanthroline ligands and its application to enantioselective addition of
organozinc reagents to aldehydes, Chem. Commun. (2014) 13224–13227.
doi:10.1039/C4CC05020G.
[16] S. Karabuga, I. Karakaya, S. Ulukanli, 3-Aminoquinazolinones as chiral ligands in catalytic
enantioselective diethylzinc and phenylacetylene addition to aldehydes, Tetrahedron
Asymmetry. 25 (2014) 851–855. doi:10.1016/j.tetasy.2014.04.019.
[17] W. Zhang, R. Tang, H. Yu, S. Gao, Efficient asymmetric addition of diethylzinc to
aldehydes using C2 -novel chiral pyridine β-amino alcohols as chiral ligands, Appl.
Organomet. Chem. 28 (2014) 545–551. doi:10.1002/aoc.3161.
[18] Y. Gök, L. Kekeç, Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed
by C2-symmetric chiral diols, Tetrahedron Lett. 55 (2014) 2727–2729.
doi:10.1016/j.tetlet.2014.03.058.
[19] M. Asami, N. Miyairi, Y. Sasahara, K.I. Ichikawa, N. Hosoda, S. Ito, Enantioselective
addition of diethylzinc to aldehydes catalyzed by (R)-1-phenylethylamine-derived 1,4-amino
alcohols, Tetrahedron. 71 (2015) 6796–6802. doi:10.1016/j.tet.2015.07.031.
[20] S. Celik, M. Cakici, H. Kilic, E. Sahin, Synthesis of quinazolinone-based aziridine diols as
chiral ligands: Dual stereoselectivity in the asymmetric ethylation of aryl aldehydes,
Tetrahedron Asymmetry. 26 (2015) 152–157. doi:10.1016/j.tetasy.2014.12.011.
[21] F. Li, H. Huang, H. Zong, G. Bian, L. Song, Investigation on the asymmetric addition
reactions between varied nonaromatic aldehydes and diethylzinc catalyzed by chiral
phosphoramide and thiophosphorodiamide ligands, Tetrahedron Lett. 56 (2015) 2071–
2076. doi:10.1016/j.tetlet.2015.03.020.
[22] D.S. Lee, S.M. Chang, C.Y. Ho, T.J. Lu, Enantioselective addition of diethylzinc to
aldehydes catalyzed by chiral O,N,O-tridentate phenol ligands derived from camphor,
Chirality. 28 (2016) 65–71. doi:10.1002/chir.
[23] K.-D. Huynh, H. Ibrahim, L. Bouchardy, C. Bournaud, E. Kolodziej, M. Toffano, G. Vo-
Thanh, Biosourced Ligands from Isosorbide for the Ethylation of Aldehydes or Alkynylation
of Imines, Asian J. Org. Chem. 5 (2016) 1242–1246. doi:10.1002/ajoc.201600291.
[24] M.E.S. Serra, D. Murtinho, V. Paz, Enantioselective alkylation of aromatic aldehydes with
(+)-camphoric acid derived chiral 1,3-diamine ligands, Tetrahedron Asymmetry. 28 (2017)

ACCEPTED MANUSCRIPT
381–386. doi:10.1016/j.tetasy.2017.01.013.
[25] L. Pisani, S. Superchi, A. D’Elia, P. Scafato, C. Rosini, Synthetic approach toward cis-
disubstituted γ- and δ-lactones through enantioselective dialkylzinc addition to aldehydes:
application to the synthesis of optically active flavors and fragrances, Tetrahedron. 68
(2012) 5779–5784. doi:10.1016/j.tet.2012.05.028.
[26] M.A. Aga, B. Kumar, A. Rouf, B.A. Shah, S.C. Taneja, Vasicine as tridentate ligand for
enantioselective addition of diethylzinc to aldehydes, Tetrahedron Lett. 55 (2014) 2639–
2641. doi:10.1016/j.tetlet.2014.03.002.
[27] M.M. Zanardi, A.G. Suárez, Synthesis of new chiral 1,3-aminoalcohols derived from
levoglucosenone and their application in asymmetric alkylations, Tetrahedron Lett. 56
(2015) 3762–3765. doi:10.1016/j.tetlet.2015.04.051.
[28] C. Nottingham, R. Benson, H. Müller-Bunz, P.J. Guiry, Synthesis of ferrocene oxazoline
N,O ligands and their application in asymmetric ethyl- and fhenylzinc additions to
aldehydes, J. Org. Chem. 80 (2015) 10163–10176. doi:10.1021/acs.joc.5b01766.
[29] M. Asami, A. Hasome, N. Yachi, N. Hosoda, Y. Yamaguchi, S. Ito, Enantioselective
addition of diethylzinc to aldehydes catalyzed by o-xylylene-type chiral 1,4-amino alcohols
with an aminal structure, Tetrahedron Asymmetry. 27 (2016) 322–329.
doi:10.1016/j.tetasy.2016.03.007.
[30] Z. Szakonyi, Á. Csör, A. Csámpai, F. Fülöp, Stereoselective synthesis and modelling-
driven optimisation of carane-based aminodiols and 1,3-oxazines as catalysts for the
enantioselective addition of diethylzinc to benzaldehyde, Chem. Eur. J. 22 (2016) 7163–
7173. doi:10.1002/chem.201600749.
[31] M. Schubert, Compounds of thiol acids with aldehydes, J. Biol. Chem. 114 (1936) 341–
350.
[32] S.H. Kim, S.J. Ahn, S.T. Chung, M.J. Jin, New chiral catalyst for asymmetric alkylation of
aldehydes with diethylzinc, J. Ind. Eng. Chem. 3 (1997) 37–38. doi:10.1016/S0040-
4039(97)01433-0.
[33] Q. Meng, Y. Li, Y. He, Y. Guan, Novel thiazolidine derivatives as chiral catalysts in the
enantioselective addition of diethylzinc to aldehydes, Tetrahedron: Asymmetry. 11 (2000)
4255–4261. doi:10.1016/S0957-4166(00)00391-8.
[34] M.J. Jin, S.H. Kim, Enantioselective addition of diethylzinc to aldehydes with easily
prepared chiral thiazolidine catalysts, Bull. Korean Chem. Soc. 23 (2002) 509–510.
doi:10.5012/bkcs.2002.23.3.509.
[35] N.C.T. Tavares, Thiazolidines: From Enantioselective Catalysis to Molecular Dynamics,
Masters Thesis, University of Coimbra, 2016.
[36] M.E.S. Serra, D. Costa, D. Murtinho, N.C.T. Tavares, T.M.V.D. Pinho e Melo, D-
Penicillamine and L-cysteine derived thiazolidine catalysts: an efficient approach to both
enantiomers
doi:10.1017/CBO9781107415324.004.
[37] L. Sola, K.S. Reddy, A. Vidal-Ferran, A. Moyano, M.A. Pericás, A. Riera, A. Alvarez-
of
secondary alcohols,
Tetrahedron.
72
(2016)
5923–5927.

ACCEPTED MANUSCRIPT
Larena, J.-F. Piniella, A superior, readily available enantiopure ligand for the catalytic
enantioselective addition of diethylzinc to α-substituted aldehydes, Lithium. 3263 (1998)
7078–7082. doi:10.1021/jo981336i.
[38] C. Cardellicchio, G. Ciccarella, F. Naso, F. Perna, P. Tortorella, Use of readily available
chiral compounds related to the betti base in the enantioselective addition of diethylzinc to
aryl aldehydes, Tetrahedron. 55 (1999) 14685–14692. doi:http://dx.doi.org/10.1016/S0040-
4020(99)00914-X.
[39] A.L. Braga, H.R. Appelt, P.H. Schneider, C.C. Silveira, L.A. Wessjohann, A new
functionalized, chiral disulfide derived from L-cysteine: (R,R)- bis[(3-benzyloxazolan-4-yl)-
methane] disulfide as a catalyst in the diethylzinc addition to aldehydes, Tetrahedron
Asymmetry. 10 (1999) 1733–1738. doi:10.1016/S0957-4166(99)00145-7.
[40] W.M. Dai, H.-J. Zhu, X.-J. Hao, Chiral ligands derived from abrine. Part 6: Importance of a
bulky N-alkyl group in indole-containing chiral β-tertiary amino alcohols for controlling
enantioselectivity in addition of diethylzinc toward aldehydes, Tetrahedron Asymmetry. 11
(2000) 2315–2337. doi:10.1016/S0957-4166(00)00189-0.
[41] T. Tanaka, Y. Sano, M. Hayashi, Chiral Schiff bases as highly active and enantioselective
catalysts in catalytic addition of dialkylzinc to aldehydes, Chem. Asian. J. 3 (2008) 1465–
1471. doi:10.1002/asia.200800132.
[42] K. Michigami, M. Hayashi, Enantioselective alkylation of aldehydes using dialkylzincs
catalyzed by simple chiral diols derived from naturally occurring monosaccharides,
Tetrahedron. 69 (2013) 4221–4225. doi:10.1016/j.tet.2013.03.090.
[43] D. Murtinho, M.E.S. Serra, A.M. d’A. R. Gonsalves, Enantioselective ethylation of
aldehydes with 1,3-N-donor ligands derived from (+)-camphoric acid, Tetrahedron:
Asymmetry. 21 (2010) 62–68. doi:10.1016/j.tetasy.2009.12.012.
[44] T.L. Gilchrist, A.M. d’A. R. Gonsalves, T.M.V.D. Pinho e Melo, Diels-alder reactions of 2-
azadienes derived from cysteine and serine methyl ester and aldehydes, Tetrahedron Lett.
50 (1994) 13709–13724. doi:10.1016/S0040-4039(00)60625-1.
[45] G.T. Wondrak, M.K. Jacobson, E.L. Jacobson, Antimelanoma activity of apoptogenic
carbonyl
scavengers.,
J.
Pharmacol.
Exp.
Ther.
316
(2006)
805–814.
doi:10.1124/jpet.105.094953.
[46] M. Calmes, F. Escale, F. Paolini, Viable use of 2-substituted thiazolidine-4-methanol
diastereoisomeric mixtures during asymmetric borane reduction of aromatic ketones,
Tetrahedron: Asymmetry. 8 (1997) 3691–3697. doi:10.1016/S0957-4166(97)00480-1.
[47] H.T. Nagasawa, D.J.W. Goon, F.N. Shirota, Epimerization at C-2 of 2-substituted
thiazolidine-4-carboxylic acids, J. Heterocycl. Chem. 18 (1981) 1047–1051.
doi:10.1002/jhet.5570180538.
[48] B. Refouvelet, J.F. Robert, J. Couquelet, P. Tronche, Thiazolidine-2,4-dicarboxylic acid and
its esters: Synthesis, in solution behaviour and regioselective cyclocondensation, J.
Heterocycl. Chem. 31 (1994) 77–80. doi:10.1002/jhet.5570310114.
[49] T.M.V.D. Pinho e Melo, M.I.L. Soares, A.M. d’A. R. Gonsalves, J.A. Paixão, E. Al.,

ACCEPTED MANUSCRIPT
Synthesis of chiral pyrrolo [1,2-c] thiazoles via intramolecular dipolar cycloaddition of
müchnones: An interesting rearrangement to pyrrolo [1,2-c] thiazines, J. Org. Chem. 67
(2002) 4045–4054. doi:10.1021/jo010807p.
[50] H. Brunner, R. Becker, G. Riepl, Asymmetric Syntheses. 20. Enantioselective
hydrosilylation of ketones with [Rh(cod)Cl]2/Thiazolidine Catalysts, Organometallics. 3
(1984) 1354–1359. doi:10.1021/om00087a006.
[51] C. Bolm, K. Muñiz, J.P. Hildebrand, Planar-chiral ferrocenes in asymmetric catalysis: The
impact of stereochemically inhomogeneous ligands, Org. Lett. 1 (1999) 491–493.
doi:10.1021/ol990683r.
[52] F. Neese, The ORCA program system, WIREs Comput. Mol. Sci. 2 (2012) 73–78.
doi:10.1002/wcms.81.
[53] R. Noyori, S. Suga, K. Kawai, S. Okada, M. Kitamura, Enantioselective alkylation of
carbonyl compounds. From stoichiometric to catalytic asymmetric induction, Pure Appl.
Chem. 60 (1988) 1597–1606. doi:10.1351/pac198860111597.
[54] C. Adamo, V. Barone, Toward chemical accuracy in the computation of NMR shieldings:
The PBE0 model, Chem. Phys. Lett. 298 (1998) 113–119. doi:10.1016/S0009-
2614(98)01201-9.
[55] T.H. Dunning, Gaussian basis sets for use in correlated molecular calculations. I. The
atoms boron through neon and hydrogen, J. Chem. Phys. 90 (1989) 1007–1023.
doi:10.1063/1.456153.
[56] D.E. Woon, T.H. Dunning, Gaussian basis sets for use in correlated molecular calculations.
III. The atoms aluminum through argon, J. Chem. Phys. 98 (1993) 1358–1371.
doi:10.1063/1.464303.
[57] N.B. Balabanov, K.A. Peterson, Systematically convergent basis sets for transition metals.
I. All-electron correlation consistent basis sets for the 3d elements Sc-Zn, J. Chem. Phys.
123 (2005) 64107-1–15. doi:10.1063/1.1998907.

ACCEPTED MANUSCRIPT
Chiral Thiazolidines in the Enantioselective Ethylation of Aldehydes: An
Experimental and Computational Study
Nélia C. T. Tavares, César T. Neves, Bruce F. Milne, Dina Murtinho, Alberto A. C. C. Pais and
M. Elisa Silva Serra*
D-Penicillamine and L-cysteine derived thiazolidines were obtained through a simple
microwave procedure and used in the enantioselective alkylation of aldehydes with diethylzinc,
giving (S) and (R) enantiomers of the product alcohols with ee up to 94%. NMR and
computational studies gave important insight into the species involved in the catalytic cycle.

ACCEPTED MANUSCRIPT
Highlights
•
•
•
•
•
Chiral thiazolidines prepared from L-cysteine/D-penicillamine with MW irradiation.
Enantioselective ethylation of aromatic aldehydes gave ee up to 94%.
Enantioselective ethylation of heteroaromatic/aliphatic substrates gave ee up to 77%.
Interesting approach for obtaining both the (S) and (R) chiral alcohols.
NMR and Computational studies gave insight into catalytic species.