Highly efficient small organic molecules for enantioselective direct aldol reaction in organic and aqueous media

Article abstract of DOI:10.1021/jo900548f

(Chemical Equation Presented) A series of highly efficient organocatalysts have been derived from naturally available amino acids for carrying out enantioselective direct aldol reaction in both organic and aqueous medium. The aldol products were obtained in high diastereoselectivities (up to 99:1) and enantioselectivities (up to >99% ee) for a broader range of substrates using 1 mol % of a catalyst. The results demonstrate that the structural features of organocatalysts play a crucial role in obtaining high optical purity of aldol adducts in an aqueous medium. Further, the role of water in increasing the rate and enantioselectivity of the reaction has been illustrated. Moreover, the aldol products have been employed in the synthesis of chiral amino alcohols which act as useful intermediates for building up complex natural products.

Full text of DOI:10.1021/jo900548f

Highly Efficient Small Organic Molecules for Enantioselective Direct
Aldol Reaction in Organic and Aqueous Media
Monika Raj Vishnumaya and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Vinodks@iitk.ac.in
ReceiVed March 12, 2009
A series of highly efficient organocatalysts have been derived from naturally available amino acids for
carrying out enantioselective direct aldol reaction in both organic and aqueous medium. The aldol products
were obtained in high diastereoselectivities (up to 99:1) and enantioselectivities (up to >99% ee) for a
broader range of substrates using 1 mol % of a catalyst. The results demonstrate that the structural features
of organocatalysts play a crucial role in obtaining high optical purity of aldol adducts in an aqueous
medium. Further, the role of water in increasing the rate and enantioselectivity of the reaction has been
illustrated. Moreover, the aldol products have been employed in the synthesis of chiral amino alcohols
which act as useful intermediates for building up complex natural products.
Introduction
design of new chiral organocatalysts,2 mainly for two reasons:
first, one can avoid the use of transition metals in the reaction,
and second, the reaction can directly be done by taking aldol
donors and acceptors.3 The latter objective has been achieved
previously with the use of heterobimetallic catalysts,4 where
preactivation of carbonyl compounds, like in the asymmetric
Mukaiyama aldol reaction,5 was not required. Proline has long
been known for its use in asymmetric intramolecular aldol
reaction.6 The major breakthrough came from the findings by
List,7 Barbas,8 and co-workers that L-proline could also act as
a catalyst in the intermolecular direct aldol reaction. It functions
as a “microaldolase” similar to type I aldolase enzyme.9 Since
Enantioselective C-C bond formation reaction catalyzed by
chiral organic molecule (asymmetric organocatalysis)1 has
become an important area of research in organic synthesis. Aldol
is one such reaction where a great emphasis has been given to
* To whom correspondence should be addressed. Fax: +91-512-2597436.
(1) For special issues on asymmetric organocatalysis, see: (a) List, B. Chem.
ReV. 2007, 107, 5413. (b) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. ReV. 2003,
103, 3401. (c) List, B.; Bolm, C. AdV. Synth. Catal. 2004, 346, 1007. (d) Houk,
K. N.; List, B. Acc. Chem. Res. 2004, 37, 487. (e) List, B. Chem. Commun.
2006, 819. (f) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.;
Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. (g) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481. (h) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007,
107, 5713. (i) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
For reviews, see: (j) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res.
2004, 37, 580. (k) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew.
Chem., Int. Ed. 2008, 47, 6138. (l) Emsley, J. Chem. Soc. ReV. 1980, 9, 91. (m)
Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315. (n) Erkkila, A.;
Majander, I.; Pihko, P. M. Chem. ReV. 2007, 107, 5416. (o) Mukherjee, S.; Yang,
J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (p) Barbas, C. F.,
III. Angew. Chem., Int. Ed. 2008, 47, 42. (q) Gaunt, M. J.; Johansson, C. C. C.;
McNally, A.; Vo, N. T. Drug DiscoVery Today 2007, 12, 8. (r) de Figueiredo,
R. M.; Christmann, M. Eur. J. Org. Chem. 2007, 2575. (s) Enders, D.; Grondal,
C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (t) Ting, A.; Schaus,
S. E. Eur. J. Org. Chem. 2007, 5797. (u) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701. (v) Marigo, M.; Jorgensen, K. A. Chem. Commun. 2006, 2001. (w)
Cozzi, F. AdV. Synth. Catal. 2006, 348, 1367. (x) Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719. (y) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138. (z) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
(2) For reviews on asymmetric aldol reaction using chiral organocatalysis,
see: (a) List, B. Acc. Chem. Res. 2004, 37, 548. (b) Allemann, C.; Gordillo, R.;
Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558.
(c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570. (d) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2006, 45, 958. (e) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed.
2003, 42, 858. (f) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH:
Weinheim, 2004; Vols. 1 and 2.
(3) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Alcaide, B.; Almendros, P. Angew.
Chem., Int. Ed. 2003, 42, 858. (c) Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004; Vols. 1 and 2.
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10.1021/jo900548f CCC: $40.75
Published on Web 05/07/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4289–4297 4289

Vishnumaya and Singh
FIGURE 2. Design of new chiral organocatalysts.
FIGURE 1. Transition-state models.
then, L-proline10 and its derivatives11 have been evaluated for
use in enantioselective direct aldol reaction.
Organocatalyzed aldol reaction is presumed to proceed via
an enamine intermediate. Initially, the enantiofacial selectivity
wasexplainedwithametal-freeversionoftheZimmerman-Traxler
six-membered ring chairlike model12 having a tricyclic hydrogen-
bonded framework (Figure 1).7a Later, based on DFT calcula-
tions, the transition-state model was modified (Figure 1). This
model indicates that the nitrogen of L-proline does not participate
in hydrogen bonding with the carboxylic hydrogen, resulting
in a nine-membered-ring-like transition state.13 Second, enamine
FIGURE 3. L-Proline-based organocatalysts.
formed should be anti to the carboxylic group, and in this anti
arrangement, NCH--O also contributes to lowering the energy
of the transition state [NCH--O (anti) distance ) 2.44 Å vs
NCH--O (syn) distance ) 3.42 Å]. The main aspect of this
model is that the transition state is stabilized through hydrogen
bondings. Therefore, a small change in the pKa value of an
organic compound would affect its catalytic activity and
selectivity in the aldol reaction.
It is a great challenge for organic chemists to find a suitable
organic compound with an optimal pKa so that excellent
enantioselectivity can be obtained in the reaction. One such
organic compound was synthesized by Gong et al. (A)11a (Figure
2). If the pKa value of the hydroxyl group involved in the
hydrogen bonding with the acceptor aldehyde is further in-
creased, it would result in a structurally compact transition state
that may ensure high enantioselectivity and reactivity. Based
on the above rationale, we designed a small class of L-proline-
based chiral organic molecules having a gem-diphenyl group
which played a key role in realizing the goal (B as in Figure
2).14
In this paper, we have described full details of our work in
this area. We have further synthesized a new series of small
organic compounds from L-threonine, L-serine, and L-cysteine
to determine the essential and beneficial criteria required in
organocatalyst to obtain very high optical purity for direct aldol
reaction in both organic and aqueous media. The methodology
has been applied for the synthesis of chiral amino alcohol that
acts as a useful intermediate for asymmetric organic synthesis
and for building up complex natural products.
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Mitchell, M.; Wong, C.-H.; Wilson, I. A. Science 2001, 294, 369, and references
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Wilson, I. A. J. Mol. Biol. 2004, 343, 1269, and references therein.
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Results and Discussion
At the outset, the organic compounds (1a-m) were synthe-
sized from L-proline and the corresponding ꢀ-amino alcohols
(Figure 3).14 These were evaluated as catalysts for the direct
aldol reaction between benzaldehyde and acetone (Table 1). The
reactions were done using 10 mol % of these compounds in an
excess of acetone at different temperatures. Initially, a com-
parison was made among catalysts 1a-g having different R
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4290 J. Org. Chem. Vol. 74, No. 11, 2009

Direct Aldol Reaction in Organic and Aqueous Media
TABLE 1. Direct Aldol Reaction of Benzaldehyde with Acetone
It would be a win-win situation from a green chemistry
perspective if high enantiocontrol could be achieved using small
organic molecules in water.15,16 Extensive research is going on
to design small organic molecules that can carry out the
asymmetric aldol reaction in water. Such organocatalysts were
initially reported by Barbas,17 Hayashi,18 and Chimni.19 These
catalysts have the limitation of giving moderate enantioselec-
tivity with water-miscible ketones such as acetone. The other
existing organocatalysts, which work in aqueous medium, are
also marked with few limitations such as the use of additives,17,20
high loading of the catalyst,20e,21 low substrate scope,20b,21b,22
and requirement of ketone in excess where water acts only as
an additive.20a,d,e,23 Therefore, there is a great need for a chiral
organocatalyst, which can surpass these drawbacks and which
could be efficient from the viewpoint of both catalysis and
reactivity.
For a catalyst to work preferentially well in an aqueous
medium, it should contain sufficient hydrophobic groups. Our
prolinamide catalysts (1d and 1g) bearing nonpolar gem-
diphenyl group fulfill this criteria. Therefore, these were tested
for aldol reactions using water as a medium.24 The reaction of
acetone (2 mmol) with benzaldehyde (0.5 mmol) was studied
by using different loadings of the catalyst 1 (10-0.5 mol %) in
0.5 mL of water/brine. It was observed that yields and ee’s were
Catalyzed by Organocatalysts 1a-ma
entry
catalyst
T (°C)
time (h)
% yield
% eeb
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1d
1d
1e
1f
1g
1g
1g
1h
1i
-40
-40
-40
rt
48
48
26
03
14
48
24
48
06
08
22
06
30
26
48
45
06
64
52
62
68
72
52
55
53
71
76
77
65
57
67
65
57
67
89
99
92
92
98
>99
79
95
84
91
99
24
64
42
46
43
59
0
-40
-40
-40
rt
0
-40
rt
-40
-40
-40
-40
0
9
10
11
12
13
14
15
16
17
1j
1k
1l
1m
a The reaction was carried out in neat acetone (1 M) using 10 mol %
of the catalyst except for the catalysts 1g, 1i, and 1j which were used in
5 mol %. b Determined by HPLC using a chiral column.
SCHEME 1. Direct Aldol Reaction of Acetone with Various
Aldehydes
(15) For a very interesting discussion on whether this kind of reaction should
be called “in water”, “on water”, “in the presence of water”, or “concentrated
organic phases”, see: (a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew.
Chem., Int. Ed. 2006, 45, 8100. (b) Hayashi, Y. Angew. Chem., Int. Ed. 2006,
45, 8103. (c) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew.
Chem., Int. Ed. 2007, 46, 2.
(16) The above phrases in using water for the reaction are a matter of
semantics. However, we prefer to use “in an aqueous medium” for our reactions.
(17) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
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Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Hayashi, Y.; Aratake, S.;
Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006,
45, 5527.
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2006, 17, 1493. (b) Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G.
Org. Lett. 2007, 9, 1247. (c) Gryko, D.; Saletra, W. J. Org. Biomol. Chem. 2007,
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Dziedzic, P.; Zou, W.; Hafren, J.; Cordova, A. Org. Biomol. Chem. 2006, 4, 38.
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groups with (S)-configuration at the R-carbon while keeping a
gem-diphenyl group constant at the ꢀ-carbon. The results
showed that the chirality at R-carbon is not essential but
beneficial for obtaining high enantioselectivity (entries 1 and
2, Table 1).
It is worth mentioning here that when the configuration of
the phenyl substituent at the R-carbon (1g vs 1h) was changed
from S to R, the enantioselectivity dropped from 84 to 24%
(entries 9 and 12). Further, to see the effect of the gem-diphenyl
group (R1) at the ꢀ-carbon, it was replaced by ethyl (1i) and H
(1j) and then evaluated for the aldol reaction. These turned out
to be poor at inducing asymmetric induction in the reaction
(entries 13 and 14; 64% ee with 1i; 42% ee with 1j). The
importance of the gem-diphenyl group at the ꢀ-carbon was
further seen in compounds 1k (R1 ) Et) and 1l (R1 ) Bn),
which gave poor asymmetric induction (entries 15 and 16;
43-46% ee) as compared to 1c (R1 ) Ph), which gave 92% ee
(entry 3) for the same reaction. When an electron-donating group
was present on the para position of the phenyl group as in the
case of 1m, the effectiveness of the catalyst was depleted (entry
17, 59% ee). From Table 1, it became clear that the organic
compounds 1d (R ) i-Bu) and 1g (R ) Ph) were found to be
the best catalysts, providing excellent enantioselectivities of
>99% at -40 °C. The advantage of catalyst 1g is that it is
effective even with low catalyst loading (5 mol %).
In order to increase the scope of the methodology, the aldol
reaction of acetone was extended to several aromatic and
aliphatic aldehydes using 1d and 1g. In all cases, excellent
enantioselectivities (97-99% ee) were obtained (Scheme 1).14
The catalyst 1d appeared to be slightly superior to 1g for
inducing enantioselectivity in all of the substrates, especially
in the case of an aliphatic aldehyde.14
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Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Lo Meo, P.; Riela, S.; Noto,
R. Eur. J. Org. Chem. 2007, 4688. (e) Giacalone, F.; Gruttadauria, M.;
Marculescu, A. M.; Noto, R. Tetrahedron Lett. 2007, 48, 255.
J. Org. Chem. Vol. 74, No. 11, 2009 4291

Vishnumaya and Singh
TABLE 2. Screening of Other Ketones and Aldehydes
SCHEME 2. Optimized Reaction Conditions
anti/syna
1d 1g
% eeb anti
SCHEME 3. Screening of Different Aromatic and Aliphatic
Aldehydes with Acetone
entry
ketone
acetone
acetone
-CH2CH2CH2- cyclohexyl 94:6 99:1
R2
1d
1g
1
2
3
4
5
i-Pr
cyclohexyl
>99
99
99
>99
>99
99
-CH2OCH2-
-CH2SCH2-
Ph
Ph
97:3 95:5
99:1 94:6
>99
>99
99
99
SCHEME 4. Screening of Different Aromatic and Aliphatic
Aldehydes with Cyclohexanone
a Determined by 1H NMR analysis of the products. b Determined by
HPLC using chiral columns.
superior in brine to those in water as the “salting out effect”
increases the “hydrophobic effect”.24,25 It was found that
reducing the catalyst loading to 0.5 mol % and decreasing the
temperature to -5 °C resulted in increased enantioselectivity
to >99% (Scheme 2). In order to show the practicality of the
method, the reaction was tested on a large scale. Acetone (2.77
mL, 37.7 mmol) was allowed to react with benzaldehyde (0.955
mL, 9.4 mmol) by using the catalyst 1d (17 mg, 0.5 mol %) in
brine (9.5 mL) at -5 °C. The reaction was completed in 24 h,
and the aldol product was obtained in 68% yield and 98.5% ee.
Having optimized the reaction conditions for enantioselective
aldol reaction in brine, it was extended to other substrates using
the catalysts 1d and 1g. A variety of aromatic and aliphatic
aldehydes were tested for the reaction using acetone as a donor
(Scheme 3). In most of the cases, excellent enantioselectivities
(98->99% ee) were obtained.
FIGURE 4. Role of stereocenter at the ꢀ-carbon atom.
SCHEME 5. Screening of New Organocatalysts
When cyclohexanone was used as a donor, high diastereo-
selectivities and excellent enantioselectivities (95-99% ee) were
obtained with different aromatic and aliphatic aldehydes (Scheme
4). It is gratifying to see that along with aromatic aldehydes,
aliphatic aldehydes such as isobutyraldehyde and cyclohexan-
carboxaldehyde also proved to be better acceptors.24 Other cyclic
ketones such as pyranone and thiopyranone were also found to
be highly active donors resulting in products with up to >99%
enantioselectivities and diastereoselectivities up to 99:1(anti/
standard reaction sequence (see the Supporting Information).
The idea behind synthesizing these catalysts was that the
presence of a planar benzene ring would bring more rigidity in
the transition state leading to high enantioselection. It was found
that the reaction of cyclohexanone with benzaldehyde in the
presence of 10 mol % of 3b at 0 °C in brine gave a maximum
of 83% ee (Scheme 5). The catalyst 3c having an electron-
donating group gave the product with lower enantioselectivity
(47%). The importance of the gem-diphenyl group was further
seen from poor enantioselectivity provided by a catalyst 3d
having diethyl substitution. The use of organic solvents also
did not make any difference in the results. The reaction did not
go with acetone as a donor. The sense of asymmetric induction
with catalysts 3a-d was same as that of catalysts 1a-m; hence,
the stereochemical outcome can be explained by similar types
of transition-state models (Figure 5).
24
syn) (Table 2).
The catalyst 1g exhibited a better catalytic performance (99%
ee) for carrying out the aldol reaction between acetone and
benzaldehyde as compared to catalyst 211a (83% ee) (Figure
4). From these results we have concluded that it is not essential
to have phenyl groups at the ꢀ-carbon atom with any particular
stereochemistry.
In order to get more information about the catalyst, it was
planned to modify the second half of the catalyst 1d to generate
a new series of organocatalysts 3a-d which can be synthesized
from L-proline and the corresponding γ-amino alcohols by a
(23) (a) Aratake, S.; Itoh, T.; Okana, T.; Usni, T.; Shoji, M.; Hayashi, Y.
Chem. Commun. 2007, 2524. (b) Nyberg, A. I.; Usano, A.; Phiko, P. M. Synlett
2004, 1891. (c) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007,
349, 812. (d) Amedjkouh, M. Tetrahedron: Asymmetry 2005, 16, 1411. (e) Peng,
F.-Z.; Shao, Z.-H.; Pu, X.-W.; Zhang, H.-B. AdV. Synth. Catal. 2008, 350, 2199.
(24) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593.
(25) For reviews on organic reactions in water, see: (a) Li, C.-J.; Chen, L.
Chem. Soc. ReV. 2006, 35, 68. (b) Li, C.-J. Chem. ReV. 2005, 105, 3095. (c)
Lindstrom, U. M. Chem. ReV. 2002, 102, 2751.
From the above results, it was found that the second half of
the catalyst 1d gave better results as compared to second half
of catalysts 3a-d. Furthermore, 1d24 having a gem-diphenyl
group worked very well in an aqueous medium (>99% ee) in
the direct aldol reaction of acetone and benzaldehyde, as
compared to proline (20 mol %, 4% ee). It was argued that the
4292 J. Org. Chem. Vol. 74, No. 11, 2009

Direct Aldol Reaction in Organic and Aqueous Media
SCHEME 6. Synthesis of New Organocatalysts
FIGURE 5. Transition-state models.
TABLE 3. Direct Aldol Reaction Catalyzed by Organocatalysts
4a-d and 5a-d
FIGURE 6. Another series of chiral organocatalysts.
entry
catalyst
solvent
% yielda
% eeb
second half of the catalyst 1d acts as a hydrophobic part and
forms a concentrated organic phase with hydrophobic reactants.
This segregates the transition state away from the water
molecules and leads to high reactivity and selectivity. In order
to tune the catalyst further, it was logical to modify the first
half and keep the second half same as in 1d. This would provide
insight about the role of the pyrrolidine ring.
1
2
3
4
5
6
7
8
4b
4b
4c
4c
4d
4d
5a
5a
5a
5b
5c
5d
acetone
brine
acetone
brine
acetone
brine
acetone
water
brine
66
50
62
48
53
45
71
75
77
72
75
78
73c
31
61
25
50
17
85
93
95
89
82
93
From Barbas’ work, it is known that the catalyst 4a7a (Figure
6) exhibited better catalytic performance (86% ee) in the aldol
reaction of acetone and p-nitrobenzaldehyde as compared to
proline7a (76% ee). This indicated the importance of the
heteroatom and substituents in the pyrrolidine ring. Thus, we
thought of combining 4b,7a 4c, and 4d with chiral diphenyl
amino alcohol so as to come up with a new series of
organocatalysts 5a-d (Figure 6). These cyclic amino acids 4b,
4c, and 4d were synthesized from L-cysteine, L-serine, and
L-threonine, respectively, and then coupled with optically active
diphenyl aminoalcohol to prepare catalysts 5a, 5b, 5c, and 5d
(Scheme 6). These organocatalysts were evaluated in the aldol
reaction of benzaldehyde and acetone (Table 3).
In accordance with our proposition, we have found that pure
amino acids and peptides having hydrophobic groups show
remarkable difference in stereoselectivity for the direct aldol
reaction in brine (Table 3). It is consistent that simple amino
acids 4b-d gave poor ee’s (entries 2, 4, and 6; 17-31% ee) as
compared to peptides 5a-d (entries 8-12; 82-95% ee) in an
aqueous medium at room temperature. This highlights the
importance of hydrophobic groups for getting high enantiose-
lectivity in an aqueous medium. Among these, 5a and 5d seemed
to be more promising than 5b and 5c.
9
10
11
12
brine
brine
brine
a Isolated yields. b Determined by HPLC using chiralpak AS-H
column. c Reference 7a.
TABLE 4. Optimization of the Reaction Conditions
catalyst
(mol %)
ketone
(equiv)
time
(h)
entry
T (°C)
% yielda
% eeb
1
2
3
4
5
6
7
8
5
2
1
0.5
1
1
1
1
4
4
4
4
2
1
4
4
rt
rt
rt
rt
rt
rt
10
0
5
7
77
76
75
70
68
60
75
74
93
96
97
97
97
96
98
>99
12
24
30
54
20
28
a Isolated yields. b Determined by HPLC using chiral columns.
In order to optimize the conditions, the catalyst 5a was chosen
arbitrarily. It was found that reducing the catalyst loading to 1
mol %, using 4 equiv of ketone, and decreasing the temperature
to 0 °C resulted in increased enantioselectivity to >99% (entry
8, Table 4). The generality of the reaction was examined in
detail using catalyst 5a for a set of different aldehydes and
ketones under the optimized reaction conditions, and the results
were summarized in Table 5. The reaction has broad applicabil-
ity with respect to aldehydes. Importantly, aliphatic aldehyde
such as isobutyraldehyde smoothly underwent reaction to give
product with high enantioselectivity of >99% (entry 4, Table
5).
J. Org. Chem. Vol. 74, No. 11, 2009 4293

Vishnumaya and Singh
TABLE 5. Screening of Different Aldehydes with Acetone
entry
R2
product
% yielda
% eeb
1
2
3
4
5
6
7
8
C6H5
4-FC6H4
6a
6b
6c
6d
6e
6f
6g
6h
6i
77
86
71
70
72
78
77
75
73
76
78
70
>99
>99
99
>99
>99
96
98
98
>99
98
99
3-OMeC6H4
i-Pr
2-Cl-6-F-C6H3
3-ClC6H4
3-FC6H4
2,5-F2C6H3
2-ClC6H4
3-BrC6H4
4-CF3C6H4
3-MeC6H4
FIGURE 8. Transition-state model.
increased, the enantioselectivity also increased gradually and
the reaction was completed in 6-8 h. It was noted that by using
50 equiv of water, the enantioselectivity reached to 97%. On
increasing the amount of water to 100 mol %, there was no
further improvement in ee. It is evident from Figure 7 that water
not only acts as a medium but also influences the rate and
enantioselectivity. Water, therefore, has a crucial role in the
transition state of these reactions.
9
10
11
12
6j
6k
6l
>99
a Isolated yields. b Determined by HPLC using chiral columns.
TABLE 6. Screening with Different Aldehydes and Ketones
The rate enhancement in water is because of the “hydrophobic
effect”,25 which is a thermodynamically favorable process due
to increase in entropy. This hydrophobic effect further increases
in brine due to the “salting out effect”25 where solute molecules
require more energy to enter into aqueous phase. This results
in the concentrated organic phase above the aqueous phase and
thus segregates the transition state away from the water
molecules resulting in high reactivity.24,25
entry
X
R2
product
anti/syna
% eeb
1
2
3
4
5
6
7
8
9
-CH2-
-CH2-
-O-
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
99:1
94:6
97:3
99:1
98:2
97:3
99:1
99:1
99:1
98:2
>99
99
>99
>99
91
96
96
>99
>99
>99
cyclohexyl
Ph
The stereochemical outcome in the direct aldol reaction
catalyzed by 5a can be explained by a transition state (Figure
8), which is based on the DFT calculations.11a,14,24 The hydrogen
bonding with NH and OH groups of the catalyst activate the
aldehyde in such a manner that C-C bond formation takes place
from its re face. The alternative si face is unfavored because of
nonbonding interactions between the R2 group and hydroxyl
group. This reaction takes place in an aqueous medium, and as
discussed above, hydrophobicity plays an important role in
increasing the rate of the reaction. Further studies of these
hydrophobic surfaces26 showed that hydroxy groups of the
surface water molecules suspended at the hydrophobic interface
might form a hydrogen bond with the amide oxygen but not
with NH and OH groups of the catalyst as they are surrounded
by hydrophobic groups, leading to transition state B as shown
in Figure 8. As compared to transition state A, the reaction via
transition state B proceeds by forming an additional hydrogen
bond, thus making amidic NH more acidic leading to compact
transition state.27 Due to this compact network, the approach
of the aldehyde from si face (C) becomes more unfavorable
(Figure 8). This explains the increase in enantioselectivity of
the aldol products in the presence of water.
-S-
Ph
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
4-OMeC6H4
2-furyl
2-naphthyl
4-CNC6H4
4-CF3C6H4
4-ClC6H4
10
7j
a Determined by 1H NMR analysis of the products. b Determined by
HPLC using chiral columns.
ꢀ-Hydroxy ketones, obtained from the direct aldol reaction
catalyzed by 5a, can generate a class of enantioenriched amino
alcohols that are very useful in organic synthesis. The diaster-
oselective reductive amination of ꢀ-hydroxy ketones 6a and 7a
was carried out with benzyl amine by using lithum aluminum
hydride28 to obtain anti-(1R,3S)-3-(benzylamino)-1-phenylbutan-
1-ol 8a in a diastereomeric ratio of 96:4 and anti-(R)-((1R,2S)-
2-(benzylamino)cyclohexyl)phenylmethanol 9a in a diastereo-
meric ratio of 98:2. The benzyl group can be further cleaved
FIGURE 7. Role of water in direct aldol reaction.
The broad scope of the catalyst 5a was further ensured by
carrying out reaction with different cyclic ketones such as
cyclohexanone, thiopyranone and pyranone that led to products
with high enantio- and diastereoselectivities (Table 6).
As the aldol reaction occurs in water/brine, we investigated
its effect on the reaction using 1 mol % of catalyst 5a, and it is
shown by graph in Figure 7. In the absence of water, the reaction
took 16 h for completion at room temperature, and the product
was obtained in 87% ee. As the ratio of water was gradually
(26) (a) Shen, Y.-R.; Ostroverkhov, V. Chem. ReV. 2006, 106, 1140. (b) Jung,
Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5429. (c) Chandrasekhar, J.;
Shariffskul, S.; Jørgensen, W. L. J. Phys. Chem. B. 2002, 106, 8078.
(27) Zhu, M.-K.; Xu, X.-Y.; Gong, L.-Z. AdV. Synth. Catal. 2008, 350, 1390.
(28) Gandhi, S.; Singh, V. K. J. Org. Chem. 2008, 73, 9411.
4294 J. Org. Chem. Vol. 74, No. 11, 2009

Direct Aldol Reaction in Organic and Aqueous Media
SCHEME 7. Synthesis of Chiral Amino Alcohols
SCHEME 9. Desymmetrization of p-Methylcyclohexanone
SCHEME 8. Application of Chiral Amino Alcohol
Moreover, diasteroselective reductive amination of ꢀ-hydroxy
ketones provide an inexpensive efficient route for the synthesis
of chiral amino alcohols that act as useful intermediates for
asymmetric organic synthesis30 and for building up complex
natural products.31-34
Experimental Section
1
General Methods. H NMR spectra were recorded on a 400
MHz spectrometer. Chemical shifts are expressed in ppm downfield
from TMS as internal standard, and coupling constants are reported
in hertz. Routine monitoring of the reaction was performed by TLC,
using precoated silica gel TLC plates. The IUPAC names of ligands
and aldol product were taken from Chem. ultra 9. All of the column
chromatography separations were done by using silica gel (100-200
mesh). Petroleum ether used was of boiling range 60-80 °C. The
organic extracts were dried over anhydrous sodium sulfate.
Evaporation of solvent was performed at reduced pressure. Brine
refers to saturated solution of NaCl in water at 25 °C. Compounds
1a-m were synthesized by our procedure.14
General Procedure for the Synthesis of Catalysts 3a-d.
Triethylamine (0.864 g, 8.54 mmol) was slowly added to a solution
of Cbz proline (8.54 mmol) in DCM (40 mL) at 0 °C. Ethyl
chloroformate (0.926 g, 8.54 mmol) was added dropwise, and the
solution was stirred at the same temperature for 15 min. Then,
optically pure amino alcohol (8.54 mmol) was added, and the
resulting solution was stirred for 10 h. The whole solution was
diluted with DCM. After filtration and removal of solvent under
reduced pressure, the residue was purified by recrystallization with
ethyl acetate. The compound obtained was then subjected to
hydrogenation in the presence of Pd/C to give pure products 3a-d
as a white solid.
by hydrogenolysis29 to give benzyl-deprotected chiral amino
alcohols (Scheme 7). The chiral amino alcohol can be cyclized
to give substituted oxazaborolidine (Scheme 8),30 which can
further be converted into oxazine31 by reaction with aldehydes.
The chiral amino alcohol can be converted into 3-hydroxypro-
line,32 tetrahydro-1, 3-oxazine-2-thione,33 and Lythraceae al-
kaloid lasubine II34 via o-benzyloxime (Scheme 8).
Furthermore, desymmetrization of p-methylcyclohexanone
was achieved by using catalyst 1d and 1g in brine at a very
low catalyst loading of 0.5 mol % with high enantioselectivity
of >99% (Scheme 9). Aldol adduct 10a was further subjected
to Bayer-Villager oxidation to generate lactone 11a.35
Conclusion
(S)-N-(2-(Hydroxydiphenylmethyl)phenyl)pyrrolidine-2-carbox-
amide (3a). This was prepared as per our general procedure to afford
In summary, we have developed a series of highly efficient
organocatalysts for enantioselective direct aldol reaction in an
aqueous medium. It has been found that the “hydrophobic
effect” plays a significant role in the aldol reaction. The results
demonstrate that the structural features of organocatalysts play
a crucial role in obtaining high optical purity of aldol adducts
in an aqueous medium. Further, the role of water in increasing
the rate and enantioselectivity of the reaction has been illustrated.
the product 3a as a white amorphous solid: yield 86%; mp 168-172
1
°C; [R]25 -91.2 (c 0.25, CHCl3); H NMR (CDCl3, 400 MHz) δ
D
1.44-1.52 (m, 3H), 1.59 (brs, -OH), 1.93-1.95 (m, 1H),
2.58-2.62 (m, 1H), 2.78-2.84 (m, 1H), 3.46-3.50 (m, 1H), 6.57
(d, J ) 7.8 Hz, 1H), 6.91-6.94 (t, J ) 7.8 Hz, 1H), 7.19-7.36
(m, 11H), 8.25 (d, J ) 8.32 Hz, 1H), 10.39 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 25.9, 30.7, 47.1, 61.2, 82.9, 123.2, 123.4,
127.7, 128.2, 128.9, 130.0, 134.9, 137.3, 145.5, 145.9, 173.8; HRMS
(TOF-ES+) calcd for C24H24N2O2 373.1917 [M + H]+, found
373.1958.
(29) Dusan, B.; Pavol, J.; Dagmar, W.; Frantisek, P.; Adam, D. Org. Biomol.
Chem. 2007, 5, 121.
(30) Kalyuskii, A. R.; Kuznecov, V. V.; Gren, A. I. Khim. Geterotsikl. Soedin.
1990, 6, 854.
(31) Kalyuskii, A. R.; Zhuchenko, S. E.; Kuznetsov, V. V.; Gren, A. I. Zh.
Org. Khim. 1989, 25, 2202.
(32) Andre, S.; Pablo, W.; Kurt, P. HelV. Chim. Acta 1996, 79, 1843.
(33) Moskovkin, A. S.; Miroshnichenko, I. V.; Unkovskii, B. V.; Petrov,
K. I. IzV. Vyssh. Uchebn. ZaVed., Khim. Khim. Tekhnol. 1983, 26, 286.
(34) Koichi, N.; Yutaka, U.; Shigeru, Y. Bull. Chem. Soc. Jpn. 1986, 59,
525.
(35) Jiang, J.; He, L.; Luo, S.-W.; Cun, L.-F.; Gong, L.-Z. Chem. Commun.
2007, 736.
(S)-N-(2-(Hydroxybis(4-trifluoromethyl)phenyl)methyl)phenyl)-
pyrrolidine-2-carboxamide (3b). This was prepared as per our
general procedure to afford the product 3b as a white amorphous
solid: yield 78%; mp 185-190 °C; [R]25D -111.2 (c 0.25, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 1.12-1.14 (m, 1H), 1.15-1.26
(m,2H), 1.40-1.46 (m, 1H), 1.67 (brs, -OH), 2.52-2.58 (m, 1H),
2.67-2.73 (m, 1H), 3.15-3.16 (m, 1H), 6.57-6.59 (dd, J ) 1.44,
8.04 Hz, 1H), 6.96-7.0 (m, 1H), 7.34-7.44 (m, 5H), 7.56-7.58
(d, J ) 8.32 Hz, 4H), 10.08 (s, 1H); 13C NMR (CDCl3, 100 MHz)
J. Org. Chem. Vol. 74, No. 11, 2009 4295

Vishnumaya and Singh
δ 25.8, 30.4, 46.9, 60.9, 81.6, 122.6, 123.6, 125.1, 127.9, 129.3,
129.6, 129.9, 134.3, 136.8, 149.2, 149.3, 173.6; HRMS (TOF-ES+)
calcd for C26H22N2O2F6 509.1663 [M + H]+, found 509.1664.
(S)-N-(2-(Hydroxybis(4-methoxyphenyl)methyl)phenyl)pyrroli-
dine-2-carboxamide (3c). This was prepared as per our general
(R)-Thiazolidine-4-carboxylic Acid (4b) (Commercially Avail-
able). This was prepared as per our general procedure to afford the
product 4b as a white solid: yield 90%; mp 220-222 °C; IR (NaCl
cell, CH2Cl2, cm-1) 1613, 3423; 1H NMR (D2O, 400 MHz) δ 3.25
(m, 2H), 4.22 (m, 1H), 4.33 (m, 2H). Anal. Calcd. for C4H7NO2S:
C, 36.08; H, 5.30. Found: C, 36.09; H, 5.32.
procedure to afford the product 3c as a white amorphous solid:
1
yield 72%; mp 170-173 °C; [R]25 -108.8 (c 0.25, CHCl3); H
(S)-Oxazolidine-4-carboxylic Acid (4c). This was prepared as per
our general procedure to afford the product 4c as a viscous liquid:
D
NMR (CDCl3, 400 MHz) δ 1.24-1.28 (m, 1H), 1.31-1.38 (m,1H),
1.44-1.56 (m, 1H), 1.89-1.96 (m, 1H), 2.57 (brs, -OH),
2.65-2.69 (m, 1H), 2.82-2.87 (m, 1H), 3.55-3.57 (m, 1H),
3.78-3.80 (m, 6H), 6.56 (d, J ) 8.0 Hz, 1H), 6.82 (d, J ) 8.5 Hz,
4H), 6.89-6.93 (t, J ) 7.5 Hz, 1H), 7.06-7.13 (m, 4H), 7.30-7.33
(t, J ) 6.4 Hz, 1H), 8.26 (d, J ) 6.8 Hz, 1H), 10.39 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 25.8, 30.6, 47.0, 55.4, 61.1, 82.5, 113.4,
123.1, 128.9, 129.9, 135.3, 137.3, 138.0, 138.3, 158.9, 173.3; HRMS
(TOF-ES+) calcd for C26H28N2O4 433.2128 [M + H]+, found
433.2129.
yield 85%; [R]25D -19.0 (c 0.5, H2O); IR (NaCl cell, CH2Cl2, cm-1
)
1
1624, 3435; H NMR (D2O, 400 MHz) δ 2.57 (s, 2H), 3.49 (m,
1H), 3.83 (m, 2H); 13C NMR (D2O, 100 MHz) δ 33.8, 67.3, 71.5,
172.7. Anal. Calcd. for C4H7NO3: C, 41.03; H, 6.03. Found: C,
41.04; H, 6.05.
(4S,5R)-5-Methyloxazolidine-4-carboxylic Acid (4d). This was
prepared as per our general procedure to afford the product 4d as
a white solid: yield 83%; mp 227-230 °C; [R]25 -28.0 (c 0.5,
D
1
H2O); IR (NaCl cell, CH2Cl2, cm-1) 1643, 3375; H NMR (D2O,
(S)-N-(2-(3-Hydroxypentan-3-yl)phenyl)pyrrolidine-2-carboxa-
mide (3d). This was prepared as per our general procedure to afford
400 MHz) δ 1.13 (d, J ) 6.6 Hz, 3H), 2.54 (s, 2H), 3.2 (d, J ) 7.6
Hz, 1H), 3.84 (m, 1H); 13C NMR (D2O, 100 MHz) δ 20.7, 33.6,
67.4, 71.4, 172.7. Anal. Calcd for C5H9NO3: C, 45.80; H, 6.92.
Found: C, 45.81; H, 6.93.
the product 3d as a white amorphous solid: yield 77%; mp 80-83
1
°C; [R]25 -76 (c 0.25, CHCl3); H NMR (CDCl3, 400 MHz) δ
D
0.77-0.88 (m, 6H), 1.69-1.80 (m, 2H), 1.85-2.04 (m, 5H),
2.13-2.20 (m, 1H), 2.43 (brs, OH), 2.99-3.05 (m, 2H), 3.79-3.82
(dd, J ) 5.4, 9.04 Hz, 1H), 6.99-7.03 (m, 1H), 7.11-7.13 (dd, J
) 1.44, 7.8 Hz, 1H), 7.22-7.26 (m, 1H), 8.40-8.42 (dd, J ) 1.24,
6.84 Hz, 1H), 11.33 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 8.1,
26.2, 31.2, 32.2, 32.5, 47.3, 61.7, 79.5, 122.4, 122.9, 127.2, 127.6,
131.8, 137.6, 173.6; HRMS (TOF-ES+) calcd for C16H24N2O2
277.1917 [M + H]+, found 277.1919.
(4R)-N-((S)-1-Hydroxy-4-methyl-1,1-diphenylpentan-2-yl)thiazo-
lidine-4-carboxamide (5a). This was prepared as per our general
procedure to afford the product 5a as a white amorphous solid:
yield 86%; mp 152-154 °C; [R]25D -59.9 (c 1.0, DMSO); IR (NaCl
cell, CH2Cl2, cm-1) 1651, 3323, 3419; 1H NMR (DMSO, 400 MHz)
δ 0.75 (d, J ) 6.6 Hz, 3H), 0.83 (d, J ) 6.4 Hz, 3H), 0.96 (m,
1H), 1.47 (m, 2H), 3.37 (m, 3H), 3.91 (m, 1H), 4.0 (m, 1H), 4.98
(t, J ) 9.8 Hz, 1H), 5.90 (bs, 1H), 7.07-7.30 (m, 6H), 7.48 (m,
4H), 7.72 (d, J ) 9.7 Hz, 1H); 13C NMR (DMSO, 100 MHz) δ
21.6, 24.0, 24.2, 35.1, 38.6, 52.8, 53.6, 65.7, 80.0, 125.3, 125.5,
126.0, 126.2, 127.5, 128.0, 146.0, 146.7, 169.8; HRMS (TOF-ES-)
calcd for C22H28N2O2S [M - H]+ 383.1793, found 383.1793.
General Procedure for the Synthesis of Catalysts 4b-d36
(Scheme 6). NaOH (2 N, 0.672 g in 8.4 mL H2O) and formaldehyde
(1.68 mL, 1.68 mmol) were added to L- serine, L-threonine, or
L-cysteine (16.8 mmol) in a round-bottom flask at 0 °C, and the
solution was stirred at the same temperature for 7 h. To this solution
were added hydroxylamine hydrochloride (0.117 g, 1.68 mmol),
acetone (9.8 mL) and NaOH solution (0.672 g, 1.68 mmol in 1.4
mL H2O) at 0 °C, and the resulting solution was stirred for 15
min. Then, di-tert-butyl dicarbonate (18.15 mmol) was added at
room temperature, and the solution was stirred for another 3 h.
After completion, the reaction mixture was diluted with water and
washed with ether. Ether extracts were discarded, and 20% citric
acid was added to aqueous layer and extracted with ethyl acetate.
The organic layer was dried, and the solvent was removed to obtain
pure 4b′-d′ as white solid. Formic acid (60 mL) was slowly added
to compound 4b′-d′ (14.3 mmol) at 0 °C, and the resulting solution
was stirred for 10 h. Excess formic acid was carefully neutralized
by adding solid sodium bicarbonate, and the whole mixture was
extracted with ethyl acetate. The organic layer was dried, and the
solvent was removed to obtain pure product as white solid.
General Procedure for the Synthesis of Catalysts 5a-d14
(Scheme 6). Triethylamine (0.864 g, 8.54 mmol) was slowly added
to a solution of compound 4b′-d′ (8.54 mmol) in DCM (40 mL)
at 0 °C. Ethyl chloroformate (0.926 g, 8.54 mmol) was added
dropwise, and the solution was stirred at the same temperature for
15 min. Then, optically pure amino alcohol (8.54 mmol) was added,
and the resulting solution was stirred for 10 h. The whole solution
was diluted with DCM. After filtration and removal of solvent under
the reduced pressure, the residue was purified by recrystallization
with ethyl acetate to give compounds 5a′-d′.
(4S,5R)-N-((S)-1-Hydroxy-4-methyl-1,1-diphenylpentan-2-yl)-5-
methyloxazolidine-4-carboxamide (5b). This was prepared as per
our general procedure to afford the product 5b as a white amorphous
solid: yield 80%; mp 124-127 °C; [R]25 -64.0 (c 1.0, DMSO);
D
IR (NaCl cell, CH2Cl2, cm-1) 1679, 3363, 3459; 1H NMR (DMSO,
400 MHz) δ 0.66 (d, J ) 6.1 Hz, 3H), 0.73 (d, J ) 7.6 Hz, 3H),
0.83 (m, 2H), 1.2 (d, J ) 7.1 Hz, 3H), 1.55 (m, 1H), 2.90 (m, 1H),
3.16 (m, 1H), 4.5 (m, 1H), 4.94 (m, 1H), 5.04 (t, J ) 9.8 Hz, 1H),
5.67 (bs, 1H), 7.07-7.42 (m, 6H), 7.51 (m, 4H), 7.79 (d, J ) 9.5
Hz, 1H); 13C NMR (DMSO, 100 MHz) δ 21.4, 23.8, 24.1, 27.8,
38.5, 52.9, 63.9, 78.6, 79.6, 80.2, 125.1, 125.2, 126.1, 126.2, 127.6,
128.1, 145.9, 146.9, 172.5; HRMS (TOF-ES-) calcd for C23H30N2O3
[M - H]+ 381.2178, found 381.2173.
(4S)-N-((S)-1-Hydroxy-4-methyl-1,1-diphenylpentan-2-yl)oxazo-
lidine-4-carboxamide (5c). This was prepared as per our general
procedure to afford the product 5c as a white amorphous solid:
yield 81%; mp 189-192 °C; [R]25D -60.9 (c 1.0, DMSO); IR (NaCl
cell, CH2Cl2, cm-1) 1644, 3355, 3438; 1H NMR (DMSO, 400 MHz)
δ 0.74 (d, J ) 6.6 Hz, 3H), 0.82 (d, J ) 6.4 Hz, 3H), 0.92 (m,
1H), 1.45 (m, 2H), 2.91 (m, 1H), 3.02 (m, 1H), 3.16 (m, 1H), 4.58
(m, 1H), 4.91 (m, 2H), 5.95 (bs, 1H), 7.06-7.29 (m, 6H), 7.47 (m,
4H), 7.75 (d, J ) 10 Hz, 1H); 13C NMR (DMSO, 100 MHz) δ
21.6, 23.9, 24.2, 27.8, 38.6, 53.1, 57.2, 64.1, 80.1, 125.3, 125.7,
126.3, 126.5, 127.4, 127.9, 146.3, 146.7, 172.5; HRMS (TOF-ES-)
calcd for C22H28N2O3 [M - H]+ 367.2022, found 367.2021.
(4S)-N-((S)-2-Hydroxy-1,2,2-triphenylethyl)oxazolidine-4-car-
boxamide (5d). This was prepared as per our general procedure to
afford the product 5d as a white amorphous solid: yield 76%; mp
218-221 °C; [R]25D -142.7 (c 1.0, DMSO); IR (NaCl cell, CH2Cl2,
cm-1) 1640, 3389, 3468; 1H NMR (DMSO, 400 MHz) δ 3.07 (m,
2H), 3.21 (m, 1H), 4.60 (m, 1H), 4.81 (m, 1H), 5.78 (d, J ) 8.5
Hz, 1H), 6.18 (bs, 1H), 6.99-7.21 (m, 11H), 7.29 (t, J ) 7.5 Hz,
2H), 7.49 (d, J ) 7.6 Hz, 2H), 8.59 (d, J ) 9.8 Hz, 1H); 13C NMR
(DMSO, 100 MHz) δ 56.8, 58.5, 64.0, 79.9, 111.4, 126.0, 126.2,
Formic acid (40 mL) was slowly added to compounds 5a′-d′
(7.3 mmol) at 0 °C, and the resulting solution was stirred for 10 h.
Excess formic acid was carefully neutralized by addition of solid
sodium bicarbonate, and the whole mixture was extracted with ethyl
acetate. The organic layer was dried, and the solvent was removed
to obtain yellow solid which was further purified by recrystallization
with ethyl acetate to obtain pure product 5a-d as white solid.
(36) Falorni, M.; Conti, S.; Giacomelli, G.; Cossu, S.; Soccolini, F.
Tetrahedron: Asymmetry 1995, 6, 287.
4296 J. Org. Chem. Vol. 74, No. 11, 2009

Direct Aldol Reaction in Organic and Aqueous Media
126.3, 126.5, 126.7, 127.2, 127.7, 129.1, 139.6, 145.2, 146.3, 171.9;
HRMS (TOF-ES-) calcd for C24H24N2O3 [M - H]+ 387.1709, found
387.1706.
Supporting Information Available: General experimental
procedures, characterization data including 1H NMR spectra,
13C NMR spectra for all compounds, and HPLC chromato-
grams for compounds 6a-l, 7a-j, 12a, and 13a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. V.K.S. thanks the Department of Science
and Technology, India, for a research grant. M.R. and V.M.
thank the Council of Scientific and Industrial Research, New
Delhi, for a senior research fellowship.
JO900548F
J. Org. Chem. Vol. 74, No. 11, 2009 4297