Thiazolidine-based organocatalysts for a highly enantioselective direct aldol reaction

Article abstract of DOI:10.1016/j.tetasy.2010.07.028

A set of enantiopure thiazolidine-based organocatalysts have been synthesized from l-cysteine, in a straightforward manner allowing numerous structural variations. In particular, organocatalyst 3a exhibits the highest catalytic performance working in an a

Full text of DOI:10.1016/j.tetasy.2010.07.028

Tetrahedron: Asymmetry 21 (2010) 2254–2257
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Tetrahedron: Asymmetry
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Thiazolidine-based organocatalysts for a highly enantioselective direct
aldol reaction
⇑
Raoní S. Rambo, Paulo H. Schneider
Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, C.P. 15003, 91501-970 Porto Alegre-RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2010
Accepted 22 July 2010
A set of enantiopure thiazolidine-based organocatalysts have been synthesized from L-cysteine, in a
straightforward manner allowing numerous structural variations. In particular, organocatalyst 3a exhib-
its the highest catalytic performance working in an aqueous medium. It catalyzed the direct catalytic
asymmetric intermolecular aldol reaction between unmodified ketones and an aldehyde with excellent
stereocontrol and furnished the corresponding aldol products in up to 99% ee. Compound 3a also showed
excellent asymmetric catalytic activity in the asymmetric Michael reaction (up to 99% ee).
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
been successfully used as chiral ligands in several organometallic
reactions. For example Braga et al. have reported their use as
The first asymmetric reaction in which low molecular weight
organic molecules were used as catalysts was an intramolecular
highly efficient ligands for the enantioselective addition of diethyl-
zinc10 or alkynylzinc11 to aldehydes, as well as in the asymmetric
palladium-catalyzed allylic alkylation.12 In general the products
were obtained with excellent enantiomeric excesses.
As part of our broader program to explore the preparation and
use of chiral catalysts in asymmetric synthesis, we herein report
the synthesis of a class of chiral thiazolidine-derived organocata-
lysts (Scheme 1) and their application in the organocatalytic asym-
metric aldol reaction. The first evaluation of their catalytic activity
on the asymmetric Michael reaction is also reported.
asymmetric aldol reaction of a triketone catalyzed by L-proline
and was reported by two industrial research groups in 1971.1,2
Although this chemical transformation using organocatalysts has
been documented sporadically since then, it was only in the late
1990s that this research area has experienced an exponential
growth. More precisely since the prior work of List,3 Barbas4
et al. it was found that L-proline could catalyze a direct intermolec-
ular asymmetric aldol reaction. In addition some mechanistic
aspects were also investigated. They suggested that this catalyst
could act as a ‘micro aldolase’,5 activating the nucleophile through
enamine formation.2a With regards to this activation mode, two as-
pects should be noted: first it avoids the use of transition metals in
the reaction and second, the reaction can be performed directly by
using aldol donors and acceptors.6 Since then, the amino acid
2. Results and discussion
Organocatalysts 3a–d were synthesized in a short, high yielding
sequence. By using the described synthetic route, a high structural
diversity can be readily generated, which is important for the sys-
tematic optimization of a catalyst structure. Thus, (R)-cysteine was
first converted into thiazolidine carboxylic acids 1 by treatment
with formaldehyde, and a subsequent reaction with Boc2O. A dou-
ble Grignard addition or reduction of the corresponding aminoest-
ers afforded the desired aminoalcohols, which were reacted with
thiazolidine 1 in the presence of stoichiometric amounts of
ClCOOEt and NMM to give the corresponding amides 2. Removal
of the Boc group gave the desired organocatalysts 3 in good overall
yields (Scheme 1).
With the target ligands in hand, we focused our attention
toward the optimization of the aldol reactions. Organocatalyst 3a
was chosen for the optimization studies and several parameters
such as temperature, solvent, and catalyst loading were screened
in the aldol reaction between acetone and benzaldehyde. The
results are shown in Table 1.
L-proline has been studied intensively, and has been described to
catalyze more than 10 different reactions, which would render
to it the status of a privileged catalyst.7 With proline is the
most promising catalyst, various amino acids and small peptides
were also used in order to promote the direct aldol reaction and
in some cases furnished the desired product with excellent
enantioselectivities.8
On the other hand, further studies of Barbas et al.3a showed that
thiazolidine-4-carboxylic acids could also promote the aldol reac-
tion in high ee. Despite these results, there are only a few examples
where this kind of heterocycle has been employed as chiral modi-
fiers in organocatalysts.3,9 In addition, these thiazolidines have
⇑
Corresponding author. Tel.: +55 51 3308 6286; fax: +55 51 3308 7304.
E-mail address: paulos@iq.ufrgs.br (P.H. Schneider).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.028

R. S. Rambo, P. H. Schneider / Tetrahedron: Asymmetry 21 (2010) 2254–2257
2255
O
O
O
R'
1) 37% HCHO,
1M NaOH
R
1) ClCOOEt, NMM, DCM
R
HS
OH
OH
N
H
S
S
2) Boc2O
1M NaOH
1,4-Dioxane/H2O
94%
NH2.HCl
N
N
OH
R
R
2)
R'
Boc
Boc
R'
-cisteine
1
2
L
OH
NH2
78-84%
O
H
R
3a)
3b)
3c)
3d)
R = Ph, R' = Bn
R
1) 4,5M HCl/AcOEt
2) K2CO3, DCM
N
H
R = H, R' = Bn
S
R = Ph, R' = i-Pr
R = Ph, R' = CH2SCH3
N
OH
3
Scheme 1. Synthesis of the organocatalysts.
Table 2
Table 1
Solvent effect and organocatalyst evaluation
Optimization of the reaction conditions
Ph
Ph
O
O
R'
R
Ph
R
N
H
N
S
S
H
N
OH
O
O
OH
N
OH
O
O
OH
H
O
H
O
3a
H
3
(10 mol %)
H
Acetone
r.t., 120 h
Yielda (%)
ee (%)b
Entry
Catalyst
Solvent
Yielda (%)
eeb (%)
Entry
3a (mol %)
Time (h)
T (°C)
1
2
3
4
5
3a
3a
3b
3c
3d
Brine
H2O
Brine
Brine
Brine
95
92
55
70
85
99
86
99
88
88
1
2
3
4
5
6
7
5
10
20
10
10
10
10
120
120
120
48
72
120
120
rt
rt
rt
rt
rt
0
ꢀ20
75
91
94
62
76
76
71
83
82
80
76
74
84
88
a
Isolated yields.
b
Determined by HPLC using Chiralpak AD-H column and the absolute configu-
rations were determined by comparison with the literature data.13
a
Isolated yields.
b
Determined by HPLC using Chiralpak AD-H column and the absolute configu-
rations were determined by comparison with the literature data.13
Having established the optimal reaction conditions, the activity
of catalysts 3a–d was then evaluated in the direct aldol reaction
consisting of 10 mol % organocatalyst with benzaldehyde and ace-
tone at room temperature in brine. Catalyst 3a was the most effec-
tive in the asymmetric reaction, furnishing the product in excellent
yields and enantiomeric excesses up to 99% (Table 2, entry 1). By
examining the results obtained with catalyst 3b, we can conclude
that the presence of a gem-diphenyl group at the b-carbon is
crucial for a high chemical yield. When the gem-diphenyl was re-
placed by hydrogen a dramatic decrease in the yield was observed,
despite no changes on the ee being observed (Table 2; compare en-
tries 1 and 3). Catalysts 3c and 3d were also screened and revealed
to be less efficient in the asymmetric aldol reaction, furnishing the
desired products in moderate yields and ee (Table 2, entries 4 and 5).
The scope and limitations of the direct aldol reaction catalyzed
by 3a were also examined. Thus, the optimal conditions were ap-
plied to the organocatalytic reaction and a wide range of aldehydes
including both aromatic and aliphatic reacted smoothly with ace-
tone to give the aldol adducts with good to excellent enantioselec-
tivities ranging from 67% to up to 99% ee (Table 3).
In this way, the effect of catalyst loading and temperature was
first investigated in some detail for ligand 3a. Running a test exper-
iment in the presence of 5 mol % of catalyst 3a, at room tempera-
ture and using acetone as the solvent, the aldol product was
obtained in good yield and satisfactory enantiomeric excess
(Table 1, entry 1; 75% yield, 83% ee). When increasing the amount
of organocatalyst to 10 mol %, no increase in the ee was observed,
despite the chemical yield being improved. We also observed that
reaction mixtures containing 10 mol % of 3a were equally enantio-
selective as reactions containing 20 mol % (Table 1, entries 2 and
3). Carrying out the reaction in shorter reaction times, with
10 mol % of ligand, caused a dramatic decrease in the chemical
yields (Table 1, entries 4 and 5). No changes in the ee values were
observed when the temperature of the reaction was decreased
from room temperature to 0 °C or to ꢀ20 °C (entries 6 and 7).
According to previous studies,9,14 organocatalysts with hydro-
phobic groups show a remarkable difference in stereoselectivity
for the direct aldol reaction in aqueous medium or in brine.
Hence we performed the same reaction, with the optimized con-
ditions using organocatalyst 3a, and found that the enantioselec-
tivity was increased up to 99% using brine (Table 2, entry 1). In
fact brine seems to be more effective than water, furnishing the
desired product with higher yield and ee (Table 2, compare en-
tries 1 and 2).
In general, high enantioselectivies were obtained by reacting
acetone with aromatic aldehydes bearing electron-withdrawing
or electron-donating groups, with the exception of para-bromo-
benzaldehyde and meta-nitrobenzaldehyde, which furnished the
desired product in 67% and 73% ee, respectively. Remarkably, benz-
aldehyde and 1-naphthaldehyde reacted with acetone to generate

2256
R. S. Rambo, P. H. Schneider / Tetrahedron: Asymmetry 21 (2010) 2254–2257
Table 3
this organocatalyst in asymmetric transformations are currently
underway.
Organocatalytic asymmetric aldol reaction of acetone with different aldehydes
Ph
4. Experimental
O
Ph
Ph
N
4.1. General methods
S
H
N
OH
O
O
OH
H
O
1H NMR, 13C NMR, 2D-COSY NMR, and 2D-HMQC NMR spectra
were recorded on 300 MHz spectrometers Varian Inova 300 and
Varian VNMRS 300. Chemical shifts (d) are expressed in ppm
downfield from TMS as the internal standard in spectra made in
CDCl3. Coupling constants are reported in Hertz. All enantiomeric
excesses were obtained from HPLC using a chiral stationary phase
(Chiracel AD-H or OD-H columns) on a Shimadzu LC-20AT chro-
matograph. Optical rotations were carried out on a Perkin Elmer
Polarimeter 341. Infrared spectra were obtained on a Varian 640-
IR spectrometer. All the column chromatography separations were
done by using silica gel Fluka, 100–200 Mesh. Solvents were puri-
fied by usual methods.15 Other reagents were obtained from a
commercial source and used without further purification. The
organic extracts were dried over anhydrous sodium sulfate. Evap-
oration of the solvent was performed under reduced pressure.
Brine refers to saturated solution of NaCl in water at 25 °C.
3a (10 mol %)
R
H
R
Brine, r.t., 120 h
Entry
R
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Ph
95
96
88
61
58
97
55
92
88
63
99
99
81
83
67
90
73
95
80
89
1-Naphthyl
p-F–C6H4
p-Cl–C6H4
p-Br–C6H4
o-NO2–C6H4
m-NO2–C6H4
p-OMe–C6H4
p-Me–C6H4
tert-Bu
10
a
Isolated yields.
b
Determined by HPLC using Chiralpak AD-H column and the absolute configu-
rations were determined by comparison with the literature data.13
4.2. General procedure for the synthesis of catalysts 3a–d
the aldol product with extremely high enantioselectivities (Table 3,
entries 1 and 2; ee up to 99% in both cases). It is worth noting that
this methodology can also be applied to aliphatic aldehydes. When
butyraldehyde was used, the corresponding aldol product was
obtained in moderate yield and 89% ee (Table 3, entry 10).
The nature of the substrate also plays a critical role in the effi-
cacy of the catalyst. Therefore, we decided to extend the applica-
tion of catalyst 3a, which exhibited the best performance in the
asymmetric aldol reaction and the asymmetric Michael reaction.
The model reaction chosen was the Michael addition between
cyclohexanone and trans-b-nitrostyrene, with 10 mol % of ligand
3a; a high yield and enantiomeric excess up to 99% were obtained
for the syn-diastereoisomer (Scheme 2).
In a 150 mL two-necked round-bottomed flask, the N-protected
thiazolidine 1 (3.5 g, 15 mmol), anhydrous dichloromethane (30
mL), and N-methylmorpholine (1.62 mL, 15 mmol) were added un-
der an argon atmosphere at 0 °C. The solution was stirred for
30 min, then ethyl chloroformate (1.43 mL, 15 mmol) was added.
After 30 min, the aminoalcohol (15 mmol) was added and the mix-
ture was stirred for 24 h at rt. Then, the mixture was diluted in
dichloromethane (20 mL) and washed with 1 M NaOH and an
aqueous solution of NaCl. The organic layer was dried over Na2SO4
and evaporated. The residue was dissolved in ethyl acetate (60 mL)
and a solution of 4.5 M HCl in ethyl acetate (54 mL) was added
dropwise at 0 °C. The suspension was stirred for 15 min and the
solvent was then evaporated. The residue was dissolved in dichlo-
romethane and evaporated again. This procedure was repeated
three times. The residue was dissolved in a solution of DCM (1:1)
H2O, at 0 °C and neutralized with K2CO3. The organic layer was sep-
arated and the aqueous layer was washed with DCM (3 ꢁ 50 mL).
The combined organic extracts were dried over Na2SO4 and evapo-
rated. The residue was recrystallized to furnish the product.
O
O
Ph
10 mol% 3a
NO2
NO2
Ph
48h
Ph
yield. = 60%
ee = 99% (syn)
O
Ph
Ph
N
H
S
NH
OH
4.2.1. Compound 3a
Recrystallization from ethyl ether furnished a white solid. Yield
3a
80%. Mp 171–173 °C. ½a D20
ꢂ
¼ ꢀ44 (c 1, DCM). IR (FT-IR/ATR, cmꢀ1
)
1519, 1652, 3318. 1H NMR (300 MHz, CDCl3) d 7.66–7.08 (m, 15H),
4.88–4.01 (m, 1H), 3.85–3.73 (m, 2H), 3.12–3.04 (m, 2H), 2.90–
2.78 (m, 3H). 13C NMR (CDCl3, 75.5 MHz) d 171.9, 164.7, 145.9,
144.7, 138.9, 129.0, 128.5, 128.4, 128.1, 126.9, 126.8, 126.4, 125.5,
125.5, 80.8, 65.4, 60.1, 52.9, 34.9, 34.6.
Scheme 2. Asymmetric Michael reaction using chiral organocatalyst 3a.
3. Conclusions
In conclusion, a collection of thiazolidine amides derived from
different b-amino alcohols were synthesized in a straightforward
manner, which allowed us to explore the influence of electronic
and steric characteristics of our organocatalyst in order to find an
efficient catalytic system. The organocatalysts were evaluated for
their ability to catalyze the direct aldol reactions of aromatic and
aliphatic aldehydes with acetone. These results demonstrate that
the organocatalysts 3a and 3b furnished the aldol adducts in enan-
tiomeric excesses of up to 99%. Furthermore, catalyst 3a was also
applied in the asymmetric Michael addition between cyclohexa-
none and trans-b-nitrostyrene gave the product in good yield
and excellent ee (up to 99%). Further studies on the scope of
4.2.2. Compound 3b
Recrystallization from DCM furnished a white solid. Yield 65%.
Mp 136 °C. ½a 2D0
ꢂ
¼ ꢀ20 (c 1, DCM). IR (FT-IR/ATR, cmꢀ1) 1517,
1633, 3309, 3374. 1H NMR (300 MHz, CDCl3/DMSO-d6) d 7.40–7.15
(m, 6H), 4.17–4.11 (m, 2H), 4.04 (d, 1H, J = 9.9 Hz), 3.73 (dd, 1H,
J = 3.6 Hz, J = 10.8 Hz), 3.62 (dd, 1H, J = 5.7 Hz, J = 11.1 Hz), 3.40 (d,
1H, J = 10.2 Hz), 3.31 (dd, 1H, J = 4.2 Hz, J = 11.1 Hz), 3.05 (dd, 1H,
J = 7.8 Hz, J = 11.1 Hz), 2.97 (dd, 1H, J = 6.6 Hz, J = 13.8 Hz), 2.77
(dd, 1H, J = 8.7 Hz, J = 14.1 Hz). 13C NMR (CDCl3, 75.5 MHz) d 169.8,
137.4, 128.4, 127.4, 125.4, 76.6, 65.3, 61.8, 52.6, 51.4, 35.9, 34.5.

R. S. Rambo, P. H. Schneider / Tetrahedron: Asymmetry 21 (2010) 2254–2257
2257
4.2.3. Compound 3c
Acknowledgments
Recrystallization from DCM furnished a white solid. Yield 70%.
Mp 203–205 °C. ½a D20
ꢂ
¼ ꢀ73 (c 1, DCM). IR (FT-IR/ATR, cmꢀ1
)
We are grateful to the CAPES, CNPq, INCT-CMN, and FAPERGS
for the financial support. CAPES is also acknowledged for M. Sc. fel-
lowship for R.S.R.
1521, 1652, 3334. 1H NMR (300 MHz, CDCl3) d 7.61–7.13 (m,
11H), 4.86 (dd, 1H, J = 2.4 Hz, J = 10.2 Hz), 4.15 (d, 1H, J = 9.9 Hz),
3.94 (d, 1H, J = 9.9 Hz), 3.80 (dd, 1H, J = 4.8 Hz, J = 7.5 Hz), 3.29
(br, –NH), 3.07 (dd, 1H, J = 4.9 Hz, J = 10.9 Hz), 2.87 (dd, 1H,
J = 7.5 Hz, J = 10.8 Hz), 2.34 (br, –OH), 1.95–1.87 (m, 1H), 0.94–
0.86 (m, 6H). 13C NMR (CDCl3, 75.5 MHz) d 170.8, 146.2, 145.3,
128.4, 128.3, 127.0, 126.9, 125.4, 125.3, 82.1, 66.1, 58.4, 53.6,
35.5, 28.9, 22.8, 17.9.
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ꢂ
¼ ꢀ67 (c 1, DCM). IR (FT-IR/ATR, cmꢀ1
)
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4.4. Typical procedure for the Michael addition reaction
To a solution of cyclohexanone (0.26 mL, 2.5 mmol) and the cat-
alyst 3a, 1-((E)-2-nitrovinyl)benzene (74.5 mg, 0.5 mmol) was
added. The solution was stirred at room temperature for 48 h.
Then, ethyl acetate was added and the solution was washed with
water and aqueous 0.5 M HCl. The organic layer was dried over
Na2SO4, filtered, and concentrated to give the crude product, which
was purified by flash chromatography on silica gel with hexane/
ethyl acetate (80:20) as the eluant. The enantiomeric purity was
determined by HPLC on chiralpak AD-H column (hexane/2-propa-
nol 90:10.
14. De Nisco, M.; Pedatella, S.; Ullah, H.; Zaidi, J. H.; Naviglio, D.; Özdamar, Ö.;
Caputo, R. J. Org. Chem. 2009, 74, 9562.
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Pergamon Press: New York, 1980.