Protonated chiral prolinamide catalyzed enantioselective direct aldol reaction in water

Article abstract of DOI:10.1016/j.tetlet.2005.06.112

Protonated chiral prolinamide organocatalysts have been shown to catalyze an enantioselective direct aldol process in water to provide the aldol product in high yield and good enantioselectivity. The two diastereomeric catalysts (S,R)-4b and (S,S)-4c show

Full text of DOI:10.1016/j.tetlet.2005.06.112

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5617–5619
Protonated chiral prolinamide catalyzed enantioselective
direct aldol reaction in water
a,
a
b
*
Swapandeep Singh Chimni, Dinesh Mahajan and V. V. Suresh Babu
a
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
Department of Studies in Chemistry, Central College Campus, Bangalore University, Bangalore 560 001, India
b
Received 28 April 2005; revised 15 June 2005; accepted 21 June 2005
Available online 7 July 2005
Abstract—Protonated chiral prolinamide organocatalysts have been shown to catalyze an enantioselective direct aldol process in
water to provide the aldol product in high yield and good enantioselectivity. The two diastereomeric catalysts (S,R)-4b and
(
S,S)-4c show different reactivity.
Ó 2005 Elsevier Ltd. All rights reserved.
Organocatalysis is the acceleration of chemical reactions
with a substoichiometric amount of an organic com-
pound, which does not contain a metal atom. There
exist in equilibrium with the free chiral amine (Eq. 1).
This would lower the effective base strength of the cata-
lyst thus favouring iminium ion catalysis, as observed by
Spencer.
1
are very few reports of organocatalyzed synthesis in
2
aqueous media. Aqueous media predominate in biologi-
cal systems and it must have been the solvent used by
So we prepared protonated chiral prolinamides to check
our hypothesis. To our surprise, we found these mole-
cules act as effective organocatalysts for direct cross al-
dol reaction of acetone with p-nitrobenzaldehyde in
water. In this communication, we illustrate this concept
through enantioselective catalysis using phenethylamine
prolinamide hydrobromide salt.
ꢀ
Natureꢁ in prebiotic formation of simple to complex
3
molecules. A fundamental and interesting area of
research is how homochirality originated in biomole-
4
cules in water during molecular evolution. So in order
5
to develop enzyme mimics and in an attempt to under-
stand the mechanism of the chemistry of life, catalysts
having catalytic properties in water need to be
developed.
H O
2
ð1Þ
RNH3
X
RNH2
+ H
+
X
We have been interested in developing an organocata-
lyzed enantioselective aldol reaction in water involving
Initial investigations on the aldol reaction of acetone 1
and p-nitrobenzaldehyde 2 in water using catalyst 4a
6
pyrrolidine-based chiral molecules. In order to achieve
this objective, it is important to minimize the involve-
ment of general base catalysis by the pyrrolidine and
to enhance nucleophilic catalysis through the formation
of an iminium ion. Spencer and co-workers have
observed that iminium ion catalysis becomes more effec-
tive as the base strength of the amine catalysts is
(
3
20 mol %) provided aldol adduct 3 in 92% yield and
9
3% ee (Table 1, entry 1). Using proline as the catalyst,
1
0
under similar conditions gave racemic 3 in 78% yield.
Encouraged by this result, we prepared enantiomerically
pure (S,R)-4b and (S,S)-4c and performed the aldol
reaction using them as catalysts in water and obtained
3
in 45% and 39% ee, respectively (Table 1, entries 2
7
decreased. Also, it has been reported that Br o¨ nsted
and 9). The variations in the amount of water suggest
that a lower concentration of water slightly improves
the enantioselectivity (entries 2, 3 and 4). Lower catalyst
loading does not have any effect on the enantioselectiv-
ity but it results in a longer reaction time. Performing
the reaction at a lower temperature resulted in an in-
crease in the enantioselectivity to 56% (entry 6). In the
absence of water, the reaction did not occur. The same
acids enhance the catalytic ability of pyrrolidine-based
8
organocatalysts. We envisaged that such a chiral cata-
lyst, when protonated and dissolved in water, would
Keywords: Organocatalyst; Aldol; Enamine; Water; Prolinamide.
*
Corresponding author. Tel.: +91 183 225 8802x3204; fax: +91 183
25 8820; e-mail: sschimni@yahoo.com
2
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.112

5618
S. S. Chimni et al. / Tetrahedron Letters 46 (2005) 5617–5619
Table 1. Phenethylamine prolinamide HBr 4-catalyzed asymmetric aldol reaction
Entry
Catalyst (mol %)
Acetone (mL)
Water (mL)
Solvent, acetone:water
Time
Yield (%)
% ee
3
1
2
3
4
5
6
7
8
9
4a (20)
4b (20)
4b (20)
4b (20)
4b (5)
3
3
3
3
3
3
1.5
3
3
3
3
3
3
3
3
1:1
1:1
2:1
4:1
4:1
4:1
1:1
—
1:1
4:1
—
1:1
1:1
8 h
40 h
40 h
40 h
72 h
60 h
40 h
5 d
6 h
24 h
5 d
3 h
3 h
92
89
89
86
88
60
69
Traces
87
33 (R)
45 (R)
48 (R)
50 (R)
49 (R)
56 (R)
39 (R)
nd
39 (R)
38 (R)
nd
16 (R)
—
1.5
0.735
0.735
0.735
1.5
—
a
4b (20)
4b (20)
4b (20)
4c (20)
4c (20)
4c (20)
5 (20)
3
10
11
12
13
0.735
—
3
78
Traces
87
Proline (20)
3
78
a
Reaction performed at 0–4 °C.
reaction when catalyzed with phenethylamine prolina-
mide 5 in water afforded 3 in 16% ee (entry 12) highlight-
ing the importance of protonation of the catalyst in
achieving higher enantioselectivity. This study also high-
lights the difference in the reactivity and enantioselec-
tivity of the two diastereomeric catalysts (4b and 4c) in
water where 4b provided higher enantioselectivity but
showed lower reactivity, on the other hand 4c provided
lower enantioselectivity but higher reactivity. Thus, pro-
tonated phenethylamine prolinamide 4b catalyzes the
direct cross aldol reaction of 1 and 2 in water with
Further, it was decided to study the effect of solvents on
the course of the reaction. The results are given in Table
2. Solvents such as DMSO, DMF and THF slowed the
reaction rate. In the case of catalyst 4b the various sol-
vents were found to have no detrimental effect on the
enantioselectivity of the reaction but in the case of cata-
lyst 4c lower enantioselectivity was observed.
In all the studied cases, the aldol adduct 3 was found to
possess the same (R)-absolute configuration as obtained
in the aldol reactions catalyzed by L-proline in non-
1
1
5
6% enantioselectivity at 0–4 °C. To the best of our
aqueous medium. The stereochemistry of the process
can be rationalized by invoking the transition state
represented in Figure 1, involving a proton-mediated
six-membered cyclic transition state with additional
knowledge this constitutes the first report on the use
of a protonated chiral amine as an enantioselective cata-
lyst in water (Scheme 1).
H
O
(
S) R. HBr
N
H
4
O
OH
OHC
HN
O
(20 mol%)
(
R)
H O (3 mL)
2
NO2
3
NO2
1
2
a: R =
b: R =
NH
H
(S)
H
c: R =
H
N
(
S)
NH
H
N
(
R)
H
O
5
Scheme 1.
Table 2. Effect of solvent on the aldol reaction between acetone and p-nitrobenzaldehyde catalyzed by 4b/4c
Entry
Catalyst 4
Acetone (mL)
Water (mL)
Solvent (mL)
Time
Yield (%)
% ee
3
1
2
3
4
5
6
7
b
b
b
c
c
c
a
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
DMSO (1.5)
THF (1.5)
DMF (1.5)
DMF (1.5)
DMSO (1.5)
THF (1.5)
PEG (1.5)
24 h
48 h
24 h
7 h
20 h
16 h
10 d
80
78
69
71
85
85
60
40
48
39
40
26
27
32

S. S. Chimni et al. / Tetrahedron Letters 46 (2005) 5617–5619
5619
H C
(g) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–
24; For an issue dedicated to organocatalysis, see: Adv.
Synth. Catal. 2004, 346(9–10); Acc. Chem. Res. 2004,
37(8).
3
7
(R)
O
N
(
S)
2. (a) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2002,
H
1
24, 3220–3221; (b) Cordova, A.; Notz, W.; Barbas, C. F.,
N
O
III. Chem. Commun. 2002, 3024–3025; (c) Reymond, J.-L.;
Chen, Y. J. Org. Chem. 1995, 60, 6970–6979; (d) Dicker-
son, T. J.; Lovell, T.; Meijler, M. M.; Noodleman, L.;
Janda, K. D. J. Org. Chem. 2004, 69, 6603–6609; For
peptide-catalyzed enantioselective aldol reaction in water
using hydroxy acetone as donor, see: Tang, Z.; Yang, Z.
H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org.
Lett. 2004, 6, 2285–2287.
H
Br
Ar
CH3
H
Figure 1.
3
. (a) Weber, A. L. Origin Life 2001, 31, 71; (b) Krishna-
murthy, R.; Pitsch, S.; Arrhenius, G. Origin Life Evol.
Biosphere 1998, 29, 139; (c) Graaf, R. M. D.; Visscher, J.;
Schwartz, A. W. Orig. Life Evol. Biosphere 1998, 28, 271–
activation and orientation of the aldehyde by the amide
proton. The favourable hydrophobic interaction of the
aromatic groups of the catalyst and the aldehyde
enforces the asymmetric environment.
2
82; (d) Graaf, R. M. D.; Visscher, J.; Xu, Y.; Arrhenius,
G.; Schwartz, A. W. J. Mol. Evol. 1998, 47, 501–507; (e)
Sutherland, J. D.; Whitfield, J. N. Tetrahedron 1997, 53,
11493–11527.
Small peptides have proven to be promising organic
catalysts for a number of important transformations.
1
2
We evaluated the catalytic ability of two dipeptide salts,
Pro-PheÆTFA and Pro-AlaÆTFA, in water for the enantio-
selective aldol reaction. The catalyst Pro-PheÆTFA gave 3
in 38% yield and 40% ee in 10 days while Pro-AlaÆTFA
gave no reaction in the same time. The inactivity of the
latter dipeptide as compared to the former may be
because of the absence of the hydrophobic interactions
between catalyst and the aldehyde, which constitute an
integral part of the orientation and activation process.
4. (a) Pizzarello, S.; Weber, A. L. Science 2004, 303, 1151; (b)
Siegel, J. S. Chirality 1998, 10, 24–27, and references cited
therein.
5
6
. Breslow, R. Chem. Biol. 1998, 5, R27–R28.
. Chimni, S. S.; Mahajan, D. Tetrahedron 2005, 61, 5019–
5
025.
7
8
. Roberts, R. D.; Ferran, H. E.; Gula, J. M.; Spencer, T. A.
J. Am. Chem. Soc. 1980, 102, 7054–7058.
. (a) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett.
2
003, 5, 4369–4372; (b) Ji, C.; Peng, Y.; Huang, C.; Wang,
N.; Jiang, Y. Synlett 2005, 6, 986–990; For protonated
chiral diamines, see: (c) Nakadai, M.; Saito, S.; Yamam-
oto, H. Tetrahedron 2002, 58, 8167–8177; (d) Nakadai, M.;
Saito, S.; Yamamoto, H. Synlett 2001, 1245–1248; (e)
Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570; ,
For an excellent review on protonated chiral catalysts, see:
Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew.
Chem., Int. Ed. 2005, 44, 1758–1763.
In summary, we have shown that chiral protonated pro-
linamide derivatives are useful asymmetric catalysts in
water for aldol processes. This methodology addresses
environmental concerns and encompasses the principles
of Green chemistry. Further refinement of the catalytic
structure and extension of the utility of the new method-
ology to synthetically relevant organic processes are
under active investigation.
9
. Representative experimental procedure for the aldol reac-
tion: To a stirred mixture of 2 (302 mg, 2 mmol), 1
(
(
20 mmol) and water (3 mL), prolinamideÆHBr (4)
20 mol %) was added. The reaction was monitored by
Acknowledgements
TLC. The reaction was quenched with saturated ammo-
nium chloride solution and extracted with CH Cl . The
organic layer was dried over anhydrous Na SO and
2
2
S.S.C. thanks CSIR, India, for financial support (Re-
search grant No. 01/1878/03/EMR-II). DM thanks
UGC, India, for a junior research fellowship. The
support of Dr. S. C. Taneja and Dr. K. N. Singh is
gratefully acknowledged.
2
4
distilled to obtain the crude product. Column chromato-
graphy of the crude on silica gel (60–120 mesh) using a
mixture of ethyl acetate and hexane in varying proportions
6
as eluent, gave pure product 3. The enantiomeric excess
of 3 was determined on HPLC using a Chiralpak AS-H
column (IPA/hexane; 3:7).
1
0. On the refereeꢁs suggestion, the reaction of 1 and 2 was
performed in the presence of proline and HBr. Running
the reaction for 24 h did not yield any product.
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