Highly enantioselective organocatalytic direct aldol reaction in an aqueous medium

Article abstract of DOI:10.1021/ol071013l

We have demonstrated that small organic molecules 1 and 2 catalyzed the direct aldol reaction of both acyclic and cyclic ketones with different aldehydes in an excess of water/brine. Excellent enantioselectivities up to >99% and diastereoselectivities up

Full text of DOI:10.1021/ol071013l

ORGANIC
LETTERS
2007
Vol. 9, No. 13
2593-2595
Highly Enantioselective Organocatalytic
Direct Aldol Reaction in an Aqueous
Medium†
Vishnu Maya, Monika Raj, and Vinod K. Singh*
Deparment of Chemistry, Indian Institute of Technology Kanpur, India 208 016
Vinodks@iitk.ac.in
Received May 3, 2007
ABSTRACT
We have demonstrated that small organic molecules 1 and 2 catalyzed the direct aldol reaction of both acyclic and cyclic ketones with
different aldehydes in an excess of water/brine. Excellent enantioselectivities up to >99% and diastereoselectivities up to 99% with very good
yields were obtained by using much lower catalyst loadings (0.5 mol %).
The enantioselective aldol reaction catalyzed by small
organic molecules is an important C-C bond formation
reaction for which excellent enantioselectivities have been
achieved.1 The reaction is presumed to proceed via an
enamine intermediate, mimicking nature, where the type I
aldolase enzyme2 catalyzes the aldol reaction in water. It
would be a win-win situation from a green chemistry
perspective if high enantiocontrol is achieved using small
organic molecules in water.3,4 Early studies with small
organic molecules in an aqueous medium had limited success
until recently when Barbas5 and Hayashi6 independently
reported efficient proline-derived chiral catalysts which
catalyzed the aldol reaction with high enantiocontrol in the
presence of a large excess of water.7 Most of the studies
have been done with 10 mol % catalyst loading except in
one example where Hayashi has shown that the catalyst
loading can be reduced to 1 mol %, but at the cost of a longer
reaction time (2 days). Therefore, there is a great need for
efficient chiral organocatalysts, which can work at a lower
(4) 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.
(5) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
† This paper is Dedicated to Prof. (Dr.) Lutz F. Tietze, Institut fu¨r
Organische und Biomolekulare Chemie Universita¨t Go¨ttingen, Germany,
on his 65th birthday.
(1) For selected reviews on aldol and other related reactions using
asymmetric organocatalysis, see: (a) List, B. Chem. Commun. 2006, 819.
(b) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (c) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. Engl. 2004, 43, 5138. (d) Notz, W.;
Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (e) List, B.
Acc. Chem. Res. 2004, 37, 548. (f) Allemann, C.; Gordillo, R.; Clemente,
F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc.Chem. Res. 2004, 37, 558.
(2) Heine, A.; Desantis, G.; LuZ, J. G.; Mitchell, M.; Wong, C.-H.;
Wilson, I. A. Science 2001, 294, 369.
(3) 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.
(6) (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,
T.; 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.
(7) For some recent selected references on aldol reaction in water via
asymmetric organocatalysis, see: (a) Guizzetti, S.; Benaglia, M.; Raimondi,
L.; Celentano, G. Org. Lett. 2007, 9, 1247. (b) Wu, Y.; Zhang, Y.; Yu, M.;
Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417. (c) Jiang, Z.; Liang, Z.; Wu,
X.; Lu, Y. Chem. Commun. 2006, 2801. (d) Dziedzic, P.; Zou, W.; Hafren,
J.; Cardova, A. Org. Biomol. Chem. 2006, 4, 38. (e) Chimni, S. S.; Mahajan,
D. Tetrahedron: Asymmetry 2006, 17, 2108. (f) Guillena, G.; Hita, M. D.
C.; Najera, C. Tetrahedron: Asymmetry 2006, 17, 1493. (g) Fu, Y.-Q.; Li,
Z.-C.; Ding, L.-N.; Tao, J.-C.; Zhang, S.-H.; Tang, M.-S. Tetrahedron:
Asymmetry 2006, 17, 3351. (h) Pihko, P. M.; Laurikainen, K. M.; Usano,
A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62, 317.
10.1021/ol071013l CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/23/2007

loading without affecting the enantioselectivity and the
reaction time. The catalysts should also have a wide substrate
scope, with respect to both ketones and aldehydes. Herein,
we wish to disclose such small organic molecules which are
very efficient for enantioselective aldol reaction in water/
brine.
to 0.5 mol %, the reaction took a little longer time (5 h), but
the ee increased to 97% (entry 6).
It was further observed that the enantioselectivity was
>99% on lowering the temperature to 10 °C (entry 7).
Reaction of acetone was studied with a more reactive
aldehyde such as 4-nitro-benzaldehyde (entries 10-12). In
this particular case, we could obtain only up to 87% ee. To
show the practicality of the method, the reaction was tested
at 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 1 (17 mg, 0.5 mol %) in brine (9.5 mL) at -5
°C. The reaction was complete in 24 h, and the aldol product
was obtained in 68% yield and 98.5% ee.
We have recently reported that L-proline-derived organo-
catalysts 1 and 2 (Figure 1) are very effective in an organic
Having optimized the reaction conditions for enantiose-
lective aldol reaction in brine, it was extended to other
substrates using both the catalysts, 1 and 2. A variety of
aromatic aldehydes were tested for the reaction using acetone
as a donor (Table 2). In most of the cases, excellent
enantioselectivity (>99% ee) was obtained.
Figure 1. Organocatalysts evaluated in the direct aldol reaction.
medium for enantioselective direct aldol reaction between
acetone and aldehydes (under neat conditions).8 Due to
environmental concern, water should be an ideal medium
for any organic reaction.9 While working in an area for
development of new water-compatible chiral organocatalysts,
we discovered that catalysts 1 and 2 gave extraordinary
results for the direct aldol reaction in an aqueous medium.
At the outset, aldol reaction of acetone (2 mmol) and
benzaldehyde (0.5 mmol) was studied by using different
loading of the catalyst 1 (10-0.5 mol %) in 0.5 mL of water/
brine (Table 1). It was observed that yields and ee’s were
Table 2. Screening of Different Aromatic Aldehydes with
Acetone
% yielda
% eeb
entry
Ar
product
1
2
1
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
2-Cl-Ph
3-F-Ph
2,5-Di-F-C6H4
3-Cl-Ph
2-Cl-6-F-C6H4
4-F-Ph
3-OMe-Ph
4-NO2-Ph
4-CF3-Ph
3-Br-Ph
4-OMe-Ph
3-Me-Ph
2-naphthyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
72
78
80
75
73
79
75
72
78
79
70
72
71
73
83
80
85
80
85
84
80
85
80
84
75
75
72
70
>99
98
>99
99
>99
>99
>99
>99
99
>99
>99
>99
85
Table 1. Optimization of Reaction Conditions
98
>99
>99
>99
86
99
99
97
>99
92
catalyst
mol %
temp
(°C)
time
(h)
91
entry
solvent
% yielda
% eeb
>99
>99
>99
84
1
2
3
4
5
6
7
8
9
10
10
2
water
brine
water
brine
water
brine
brine
brine
brine
brine
brine
brine
rt
rt
rt
rt
rt
1.5
2
3
2
8
75
81
76
80
75
78
75
72
70
80
78
70
80
86
77
94
95
2
a Isolated yields. bThe ee’s were determined by HPLC using Chiral
columns.
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
rt
10
5
7
97
>99
>99
>99
67
86
87
-5
-10
10
-5
-10
10
12
5
10
12
Using cyclohexanone as a donor, high diastereoselectivities
and excellent enantioselectivities (96-99% ee) were obtained
with different aromatic aldehydes (Table 3). Enantioselective
aldol reaction was also extended to other ketones as donors
and aldehydes as acceptors (Table 4). Along with aromatic
aldehydes, aliphatic aldehydes such as isobutyraldehyde and
cyclohexancarboxaldehyde also proved to be better acceptors
10c
11c
12c
b
a Isolated yields. The ee’s were determined by HPLC using Chiralpak
c
AD-H columns. 4-NO2-benzaldehyde was used as substrate.
superior in brine to those in water. With 2 mol % of the
catalyst in brine at room temperature, the reaction was
complete in 2 h and the product was obtained in 80% yield
and 94% ee (Table 1, entry 4). Reducing the catalyst loading
(8) Raj, M.; Maya, V.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8,
4097.
(9) 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.
2594
Org. Lett., Vol. 9, No. 13, 2007

Table 3. Screening of Different Aromatic Aldehydes with
Table 4. Screening of Some Other Ketones and Aldehydes
Cyclohexanone
anti/syna % eeb (anti)
anti/syna
% eeb (anti)
entry
ketone
acetone
acetone
-CH2CH2CH2- cyclohexyl
R2
product
1
2
1
2
entry
Ar
product
1
2
1
2
1
2
3
4
5
ipr
cyclohexyl
5a
5b
5c
5d
5e
-
-
-
-
>99 >99
99 >99
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
94:6
95:5
>99
86
99
83
>99
99
>99
91
91
85
93
94
96
98
4-NO2-Ph
4-OMe-Ph
4-CN-Ph
4-CF3-Ph
4-Cl-Ph
86:14 87:13
94:6 99:1
97:3 95:5 >99
99:1 94:6 >99
99
99
99
99
98:2
97:3
96:4
99:1
95:5
92:8
96:4
94:6
98:2
98:2
97:3
99:1
-CH2OCH2-
-CH2SCH2-
Ph
Ph
a Diastereoselectivities were determined by 1H NMR analysis of the
products. The ee’s were determined by HPLC using Chiral columns.
b
2-furyl
2-naphthyl 4h
4g
95
95
formation. This is further facilitated by brine (salting-out
effect).13 This helps the reaction to proceed faster because
of the concentrated organic phase.
a Diastereoselectivities were determined by 1H NMR analysis of the
products. The ee’s were determined by HPLC using Chiral columns.
b
(entries 1 and 2). It is gratifying to see that excellent
enantioselectivities (99->99% ee) were obtained in all the
cases.
The stereochemical outcome in the above direct aldol
reaction catalyzed by 1 and 2 can be explained by a transition
state (Figure 2), which is based on a previous model
supported by DFT calculations.8,10 The aldehyde is activated
by hydrogen bonding with the NH and OH of the catalyst
in a manner such that C-C bond formation takes place from
its re face. The alternative si face is unfavored due to
nonbonding interaction between the R2 group and the
hydroxyl group. The presence of gem-diphenyl groups at the
â-carbon restricts the conformation and makes the hydroxyl
group a better hydrogen-bond donor. The model requires
formation of an enamine for which there is enough evidence
in the literature.11,12 It has been pointed out that general base
catalysis must be minimized to promote enantioselectivity
by an enamine mechanism in water.3a However, in our case,
it appears that reaction takes place under biphasic basic
conditions. This can be explained by using a hydrophobic
effect where the organocatalyst and substrates assemble in
water and sequester the transition state from water.5 Ag-
gregation of organic molecules excludes water from the
organic phase and drives the equilibrium toward enamine
Figure 2. Transition State Models.
In summary, we have successfully reported highly efficient
organocatalysts for an asymmetric direct aldol reaction using
both cyclic and acyclic ketones and various aldehydes in an
aqueous medium. In most of the cases, we have achieved
>99% ee by using 0.5 mol % of the catalyst in brine. The
added advantage of the catalyst is that it does not require
any acid additive to achieve high enantioselectivity.
Acknowledgment. V.K.S. thanks DST for funding the
research project. V.M. and M.R. thank CSIR for a Senior
research fellowship.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Yu, Y.-D. J. Am. Chem. Soc. 2005, 127, 9285.
OL071013L
(11) (a) List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5839 and references cited therein. (b) Bahmanyar, S.; Houk, K.
N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475.
(12) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2002, 124, 3220.
(13) (a) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966. (b) Maya, V.; Singh,
V. K. Org. Lett. 2007, 9, 1117.
Org. Lett., Vol. 9, No. 13, 2007
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