Organocatalytic asymmetric aldol reactions mediated by a cysteine-derived prolinamide

Article abstract of DOI:10.1016/j.tetlet.2008.06.031

In this Letter, a cysteine-derived prolinamide is described to act as a robust and effective organocatalyst for enantioselective aldol reactions.

Full text of DOI:10.1016/j.tetlet.2008.06.031

Tetrahedron Letters 49 (2008) 5094–5097
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Tetrahedron Letters
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Organocatalytic asymmetric aldol reactions mediated by a
cysteine-derived prolinamide
Ricardo S. Schwab a, Fábio Z. Galetto a, Juliano B. Azeredo a, Antonio L. Braga a,
c,
Diogo S. Lüdtke b, , Márcio W. Paixão
*
*
a Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
b Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, 05508-900 São Paulo, SP, Brazil
c
´
Instituto de Quımica, Universidade de São Paulo, 05508-800 São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, a cysteine-derived prolinamide is described to act as a robust and effective organocatalyst
for enantioselective aldol reactions.
Received 7 May 2008
Accepted 5 June 2008
Available online 12 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Aldol reactions
Organocatalysis
Cysteine
The search for new catalysts that display high activity and
exquisite selectivity is a major focus of current research in the field
of asymmetric synthesis. In this context, the use of chiral small
organic molecules as catalysts has recently experienced a renais-
sance and the field of asymmetric organocatalysis has become a
highly active area of research with many opportunities for discov-
ery of new reactions and their application in asymmetric
synthesis.1
employed in a number of transition metal-catalyzed asymmetric
transformations, particularly with soft metals.5,6 On the other
hand, the incorporation of a sulfur in organocatalysts is still rare,
and only a few examples are described in the literature.7 For exam-
ple, sulfur-containing organocatalysts have been used in asymmet-
ric aldol,8 Mannich,9 and Michael additions.10 To the best of our
knowledge, no catalyst with selenium has been described thus
far.11
In this context, the amino acid proline occupies a central role,
since it is described to catalyze more than 10 different enantiose-
lective C–C and C-heteroatom bond-forming reactions, which
would render to it the status of a privileged catalyst.2 However,
despite the ability of proline to successfully catalyze many asym-
metric transformations, some drawbacks still need to be overcome,
for example, its low solubility in most organic solvents, usually
high catalyst loadings and difficult tuning of its reactivity through
structural modifications. Therefore, several derivatives, based in
the proline framework that might exhibit improved reactivity
and selectivity have been synthesized and their catalytic properties
have been evaluated. In particular, secondary amides derived from
the condensation of proline and a chiral amino alcohol have found
to provide higher yields and ee’s than proline itself, in the asym-
metric aldol reaction of acetone with several aldehydes.3,4 Addi-
tionally, chiral sulfur ligands and catalysts have been successfully
In the context of our continuing interest in the development of
chiral organochalcogen compounds and their application as
ligands and catalysts in asymmetric synthesis, we describe herein
the preparation of a series of chiral cysteine-derived prolinamides
and their application in the organocatalytic asymmetric aldol reac-
tion. Additionally, for the first time, a selenium-containing chiral
molecule was evaluated in organic catalysis.
The organocatalysts 3 were synthesized in a short, high yielding
sequence, starting from N-Boc-L-proline, which reacted with the
appropriate S-alkyl- -cysteine methyl ester to afford amide 1. Dou-
L
ble Grignard addition to the ester group or reduction with sodium
borohydride, followed by removal of the Boc group delivered the
desired organocatalysts 3 in good overall yields (Scheme 1).12
First, organocatalyst 3a was chosen for optimization studies and
several parameters such as temperature, solvent, and catalyst load-
ing were screened in the aldol reaction between acetone and benz-
aldehyde and the results are depicted in Table 1. Performing the
reaction in the presence 10 mol % of 3a, at room temperature and
using acetone as the solvent, the aldol product was obtained in
only 40% ee. A decrease in the temperature resulted in an increase
* Corresponding authors. Tel.: +55 11 3091 3687; fax: +55 11 3815 4418 (D.S.L.).
E-mail addresses: dsludtke@usp.br (D. S. Lüdtke), marelloweber@gmail.com
(M. W. Paixão).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.031

R. S. Schwab et al. / Tetrahedron Letters 49 (2008) 5094–5097
5095
SR1
R2
SR1
O
O
O
R2MgBr,
Et2O
or
NaBH4
EtOH
1. N-methylmorpholine
2. Ethyl chloroformate
O
R2
N
H
2
OH
N
H
O
3.
N
Boc
N
Boc
N
Boc
OH
OMe
R1S
OMe
NH2.HCl
4. N-methylmorpholine
1
SR1
R2
R2
O
1. TFA
2. K2CO3
N
H
N
H
OH
3
Scheme 1. Synthesis of organocatalysts.
Table 1
Table 2
Optimization studies: effects of temperature, solvent, and catalyst loading in the aldol
reaction of acetone with benzaldehyde
Influence of the structure of the catalyst in the organocatalytic asymmetric aldol
reaction
SBn
O
SR1
O
Ph
Ph
N
R2
H
N
R2
O
O
OH
Ph
N
OH
O
H
H
3a
N
H
3a-i
OH
O
O
OH
Ph
O
H
Ph
(10 mol%)
4
acetone, -15 oC, 24 h
H
Ph
4
#
3a (mol %)
Solvent
Temp. (°C)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (5)
Acetone
Acetone
Acetone
Acetone
Acetonitrile
Chloroform
CH2Cl2
DMSO
THF
1,4-Dioxane
DMF
Toluene
Acetone
25
0
65
58
83
35
40
37
08
24
46
10
62
58
55
40
70
94
97
93
84
81
93
93
73
97
90
90
Entry
Catalyst
R1
R2
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Bn
Bn
Bn
Bn
Bn
Bn
Me
Et
Ph
Me
Et
Decyl
Bn
H
83
41
39
40
35
34
60
55
94
67
71
60
74
67
82
79
ꢀ15
ꢀ70
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
3g
3h
Ph
Ph
a
Isolated yield.
b
Enantioselectivities were determined by HPLC analysis and absolute configu-
rations were determined by comparison with the literature data.4
a
Isolated yield.
b
Enantioselectivities were determined by HPLC analysis and absolute configu-
rations were determined by comparison with the literature data.4
features of the sulfurated amide moiety would be responsible for
the high levels of asymmetric induction. By examining the results
depicted in Table 2, we can conclude that the presence of a gem-di-
phenyl group is crucial for a high enantioselectivity. When the
gem-diphenyl was replaced by a gem-dialkyl group, dramatic
decrease in ee could be observed (94% vs 60-74%; compare entries
1 and 2–5). The best result for the gem-dialkyl series was achieved
when R2 = Bn, which resulted in a 74% ee of the product (entry 5).
When R2 was H, the result was similar to those obtained with cat-
alysts with alkyl groups in the b-position and 4 was formed in only
34% yield and a moderate 67% ee (entry 6). Additionally, the substi-
tution pattern at the sulfur atom also plays a role in the enantio-
selectivity. The replacement of the S-Bn group by either an S-Me
or S-Et group led to a diminished level of enantioselection and a
decrease in the yield.
in the enantioselectivity of the reaction and the aldol product 4
was obtained in 94% ee, when the reaction was performed at
ꢀ15 °C. It is important to mention that the yield also increased
by carrying out the reaction at this temperature, mainly due to
suppression of side reactions such as the elimination of water from
the aldol product. Further decrease in the temperature to ꢀ70 °C
led to a slight increase in the ee (94% vs 97%; compare entries 3
and 4), but the yield dropped from 83% to only 35%. Next, the effect
of the solvent was examined. Performing the reaction in several
polar solvents such as acetonitrile, chloroform, dichloromethane,
DMSO, THF, and 1,4-dioxane always resulted in diminished yields
and ee’s, compared to the result obtained with acetone as the sol-
vent (entries 5–10). A further improvement in the enantioselectiv-
ity was achieved using DMF as solvent, and the aldol adduct was
obtained in 97% ee, although in a lower yield of 62% (entry 11).
When the solvent was changed to the apolar toluene, the product
4 was obtained with moderate yield and in ee of 90% (entry 12).
The amount of catalyst was also examined, and we observed a
decrease, in both yield and enantioselectivity, when the loading
of 3a was reduced to 5 mol %.
Further modifications in the structure of the organocatalyst
were made, by changing the chalcogen moiety (Scheme 2). First,
we prepared a catalyst derived from L-methionine in order to in-
crease the tether length between the sulfur atom and the pyrroli-
dine ring. Thus, organocatalyst 5 was prepared according to the
same strategy depicted in Scheme 1, only changing the
L-cysteine
derivative by the appropriate protected -methionine. Evaluation
L
of the behavior of the catalyst in the asymmetric addition of ace-
tone to benzaldehyde, under our optimized conditions, delivered
the aldol product in 53% yield and an ee of 82%. This result is
The best conditions determined for catalyst 3a were then
extended to catalysts 3b–h, in order to determine which structural

5096
R. S. Schwab et al. / Tetrahedron Letters 49 (2008) 5094–5097
organocatalyst 5 or 6
O
O
OH
O
O
OH
Ph
O
O
(10 mol%)
3a (10 mol%)
acetone, -15 oC, 24 h
H
Ph
H
acetone, -15 oC, 24 h
NO2
4
NO2
SMe
yield: 95 %
SeBn
Ph
anti:syn: 77:23
ee: 85 %
O
O
Ph
Ph
Ph
N
N
H
Scheme 3. Organocatalytic asymmetric aldol reaction with cyclohexanone.
H
N
H
N
H
OH
OH
5
6
50 % yield
85% ee
53 % yield
82 % ee
In summary, the results from this investigation demonstrate
that the cysteine-derived prolinamide is a robust and effective cat-
alyst for enantioselective aldol reaction. Expanding the scope of
this organocatalyst in asymmetric transformations is underway
in this laboratory.14
Scheme 2. Asymmetric aldol reaction organocatalyzed by 5 or 6. Yields and ee’s
refer to product 4.
inferior to that obtained with organocatalyst 3a (83% yield, 94% ee)
and is comparable to that obtained with 3g (R1 = Me, R2 = Ph; 60%
yield, 82% ee). These results indicate that the distance between the
sulfur atom and the pyrrolidine nucleus does not play a significant
role in the reaction outcome. Another change that was made, aim-
ing to refine the catalytic properties of our system, was the
Acknowledgments
The authors gratefully acknowledge CNPq, CAPES (Ph.D. fellow-
ship to R. S. Schwab), and FAPESP (Grant 07/02382-7 and scholar-
ship to M. W. Paixão) for financial support.
replacement of L-cysteine by their selenium analog, L-selenocys-
teine.13 In this way, organocatalyst 6 was prepared and its catalytic
behavior was tested toward our standard reaction, and the aldol
product was isolated in 50% yield and 85% ee. Direct comparison
of the results achieved using this selenium-derived prolinamide
with 3a shows that the selenium atom does not improve the effi-
ciency of the catalyst.
References and notes
1. For selected reviews on asymmetric organocatalysis, see: (a) List, B. Chem.
Commun. 2006, 819–824; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138–5175; (c) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001–
2011; (d) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79–87; (e)
Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today
2007, 12, 8–27; (f) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
5416–5470; (g) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471–5569; (h) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713–5743; (i) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. Chem. Rev. 2007,
107, 5759–5812.
The optimal conditions were employed for the organocatalytic
asymmetric aldol reaction of acetone with a broad scope of alde-
hydes and the results of this study are summarized in Table 3. In
general, high enantioselectivities (82–94% ee) were obtained with
aldehydes substituted in the 4 position, with the exception of the
para-nitrobenzaldehyde, which furnished the corresponding aldol
adduct in a moderate 64% ee. The catalytic system displays some
sensitivity toward steric effects, and ortho-substituted benzalde-
hydes resulted in slightly decreased levels of ee’s.
The aldol reaction between the 2-cyclohexan-1-one and 4-nitro
benzaldehyde also proceeded smoothly under the standard condi-
tions, affording the corresponding product in 95% yield and 77:23
of diastereomeric ratio, favoring the anti diastereomer with high
level of enantioselectivity (Scheme 3).
2. (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691–1693; (b) Limbach, M.
Chem. Biodiv. 2006, 3, 119–133.
3. (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, S.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-
D. J. Am. Chem. Soc. 2003, 125, 5262–5263; (b) Guo, H.-M.; Cun, L.-F.; Gong, L.-
Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem. Commun. 2005, 1450–1452; (c) Tang, Z.; Yang,
Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc.
2005, 127, 9285–9289; (d) Chen, X.-H.; Luo, S.-W.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.;
Jiang, Y.-Z.; Gong, L.-Z. Chem. Eur. J. 2007, 13, 689–701; (e) Xiong, Y.; Wang, F.;
Dong, S. X.; Liu, X. H.; Feng, X. M. Synlett 2008, 73–76; (f) Liu, K.; Haeu-
ssinger, D.; Woggon, W. D. Synlett 2007, 2298–2300; (g) Russo, A.; Botta, G.;
Lattanzi, A. Synlett 2007, 795–799; (h) Shi, L.-X.; Sun, Q.; Ge, Z.-M.; Zhu, Y.-Q.;
Cheng, T.-M. ; Li, R.-T. Synlett 2004, 2215–2217; (i) Tsogoeva, S. B.; Jagtap, S. B.
Synlett 2004, 2624–2626; (j) Martin, H. J.; List, B. Synlett 2003, 1901–1902.
4. (a) Raj, M.; Maya, V.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097–4099;
(b) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593–2595.
5. Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107, 5133–5209.
6. Pellissier, H. Tetrahedron 2007, 63, 1297–1330.
Table 3
Organocatalytic asymmetric aldol reaction of acetone with several aromatic alde-
hydes
7. For
a very interesting paper on the asymmetric Rauhut–Currier reaction
catalyzed by protected cysteine, see: Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc.
2007, 129, 256–267.
8. (a) Gryco, D.; Lipinski, R. Adv. Synth. Catal. 2005, 347, 1948–1952; (b) Gryco, D.;
Lipinski, R. Eur. J. Org. Chem. 2006, 3864–3876; (c) Sakthivel, K.; Notz, W.; Bui,
T., ; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260–5267.
9. (a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III. Tetrahedron Lett.
2001, 42, 199–201; (b) List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337.
10. (a) Mandal, T.; Zhao, C.-G. Tetrahedron Lett. 2007, 48, 5803–5806;
Intramolecular Michael addition: (b) Hayashi, Y.; Gotoh, H.; Tamura, T.;
Yamaguchi, H.; Masui, R.; Shoje, M. J. Am. Chem. Soc. 2005, 127, 16028–16029.
11. For review on the application of chiral organoselenium compounds in
asymmetric catalysis, see: (a) Braga, A. L.; Lüdtke, D. S.; Vargas, F.; Braga, R.
C. Synlett 2006, 1453–1466; (b) Braga, A. L.; Lüdtke, D. S.; Vargas, F. Curr. Org.
Chem. 2006, 10, 1921–1938; (c) Wirth, T. Angew. Chem., Int. Ed. 2000, 39, 3740–
3749.
SBn
O
Ph
Ph
N
H
N
H
OH
O
O
OH
R3
O
3a (10 mol%)
H
R3
acetone, -15 oC, 24 h
4a-j
Entry
Product
R3
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
Ph
83
40
53
57
56
56
35
36
94
64
61
87
85
81
82
72
4-NO2Ph
2-NO2Ph
4-ClPh
4-MePh
2-MePh
4-OMePh
2-OMePh
12. General procedure for the synthesis of compound 3a: Under an argon
atmosphere, N-methylmorpholine (1.01 g, 10 mmol) was added to a solution
of N-(tert-butoxycarbonyl)-L-proline (2.15 g, 10 mmol) in CHCl3 (100 mL) at
0 °C. After stirring for 15 min at this temperature, ethyl chloroformate (1.08 g,
10 mmol) was added dropwise and stirring was prolonged for additional
30 min at 0 °C. After this time a CHCl3 (10 mL) solution of the S-Bn-L-cysteine
4g
4h
methyl ester (2.61 g, 10 mmol) was added dropwise, followed by 1 equiv of N-
methylmorpholine and the resulting solution was stirred at 0 °C for additional
1 h and then at room temperature for 24 h. After this time the solution was
diluted with 30 mL of CHCl3, and washed with 1 M NaOH (2 ꢁ 20 mL), 1 M HCl
a
Isolated yield.
b
Enantioselectivities were determined by HPLC analysis and absolute configu-
rations were determined by comparison with the literature data.4

R. S. Schwab et al. / Tetrahedron Letters 49 (2008) 5094–5097
5097
(2 ꢁ 20 mL), and brine (20 mL). The combined organic layers were dried with
MgSO4, filtered, and concentrated. The resulting product was used without
further purification. PhMgBr (15 mmol) in Et2O (15 mL, 1 M solution) was
added to a Et2O (10 mL) solution of 1 (5 mmol) at 0 °C, and the mixture was
stirred for additional 24 h at room temperature. After this time, the reaction
mixture was quenched with aqueous saturated NH4Cl (10 mL) and extracted
with AcOEt (3 ꢁ 15 mL). The combined organic phases were dried with MgSO4,
filtered, and the solvent removed under vacuum. The crude product was
purified by flash chromatography, first eluting with hexanes and then with a
mixture of hexanes/ethyl acetate (70:30), furnishing the desired product in
60% yield. The Boc protecting group was removed by treatment with
trifluoroacetic acid (3.66 mL), which was slowly added to N-(tert-
NMR (100 MHz, CDCl3): d = 175.0, 146.1, 144.7, 138.3, 128.7, 128.4, 128.2,
127.9, 126.8, 126.7, 126.6, 125.7, 125.5, 80.6, 60.4, 57.8, 46.9, 36.7, 31.9,
30.4, 25.4. HRMS-ESI: m/z calcd for
27H30N2O2S + H+: 447.2098.
C27H30N2O2S + H+: 447.2101; found:
C
13. (a) Braga, A. L.; Vargas, F.; Galetto, F. Z.; Paixão, M. W.; Schwab, R. S.; Taube, P.
S. Eur. J. Org. Chem. 2007, 5327–5331; (b) Braga, A. L.; Schneider, P. H.; Paixão,
M. W.; Deobald, A. M.; Peppe, C.; Bottega, D. P. J. Org. Chem. 2006, 71, 4305–
4307; (c) Schneider, A.; Rodrigues, O. E. D.; Paixão, M. W.; Braga, A. L.;
Wessjohann, L. A. Tetrahedron Lett. 2006, 47, 1019–1102.
14. General procedure for the enantioselective direct aldol reaction: A solution of a
catalyst 3a (0.1 mmol) in dry acetone (1 mL) was stirred at the temperature
indicated in the tables, for 30 min. Aldehyde (1 mmol) was then added and the
resulting mixture was stirred at the same temperature for 24 h. After
completion of the reaction, as indicated by TLC, the reaction mixture was
treated with saturated aqueous ammonium chloride solution and the whole
mixture was extracted with ethyl acetate (3 ꢁ 15 mL). The organic layer was
washed with brine, dried with MgSO4, and the solvent was removed under
vacuum. The crude mixture was purified by column chromatography on silica
gel eluting with hexane–ethyl acetate (8:2) and the ee’s were determined by
HPLC analysis using Chiralcel OD-H or Chiralpak AD-H columns.
butoxycarbonyl)-L-prolinamide 2a (1 g, 1.83 mmol) at 0 °C, and the resulting
solution was stirred for 4 h at room temperature. Excess of trifluoroacetic acid
was carefully neutralized by adding solid potassium carbonate, the whole
mixture was filtered and the solvent was removed to obtain the pure product.
Analytical data for 3a: Yield: 90%;
½
a 2D0
ꢂ
ꢀ115.7 (c 1.0, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d = 8.20 (d, 1H, J = 4.2 Hz), 7.47 (m, 4H), 7.17 (m, 11H), 5.97
(br, 1H), 4.59 (t, 1H, J = 10.6 Hz), 3.58 (s, 2H), 3.47 (m, 1H), 2.93 (m, 1H), 2.78
(m, 1H), 2.62 (m, 2H), 1.85 (m, 1H), 1.44 (m, 2H), 1.27 (m, 1H). 13C