Enantioselective direct aldol reaction "on water" promoted by chiral organic catalysts

Article abstract of DOI:10.1021/ol070002p

Figure presented 1,1′-Binaphthyl-2,2′-diamine-based (S)-prolinamides in the presence of stearic acid were able to promote the direct aldol condensation of cyclohexanone and other ketones with different aldehydes in the presence of a massive amount of wate

Full text of DOI:10.1021/ol070002p

ORGANIC
LETTERS
2
007
Vol. 9, No. 7
247-1250
Enantioselective Direct Aldol Reaction
1
“
on Water” Promoted by Chiral Organic
†
Catalysts
Stefania Guizzetti, Maurizio Benaglia,* Laura Raimondi, and
‡
,‡
‡
§
Giuseppe Celentano
Dipartimento di Chimica Organica e Industriale, UniVersit a` degli Studi di Milano,
Via Golgi 19, I-20133 Milano, Italy, and Istituto di Chimica Organica, Facolta’ di
Farmacia, UniVersit a` degli Studi di Milano, Via Venezian 21, I-20133 Milano, Italy
maurizio.benaglia@unimi.it
Received January 2, 2007
ABSTRACT
1 ′-Binaphthyl-2,2′-diamine-based (S)-prolinamides in the presence of stearic acid were able to promote the direct aldol condensation of
,1
cyclohexanone and other ketones with different aldehydes in the presence of a massive amount of water in very good yields, high
diastereoselectivity, and up to 99% ee. The behavior of both C - and C -symmetric catalysts in combination with different additives was
investigated, and a preliminary experiment of recovering and recycling of the catalytic system was also attempted.
2
1
4
The use of water as reaction solvent has many positive effects
in terms of cost, safety, and environmental impact. However,
fundamental reactions of organic chemistry. However, early
studies about the use of chiral organic catalysts in aqueous
1
5
although in the past decade much effort has been put into
the study of chemical synthesis in water, only a relatively
limited number of enantioselective organic reactions can be
medium met with only limited success. Only very recently
6
7
Barbas and Hayashi reported very efficient proline-derived
chiral catalysts for the aldol condensation “in water”. After
those breakthrough contributions in the past few months,
other examples of stereoselective reactions in aqueous solvent
2
effectively carried out in this solvent. Different expedients
have been adopted to circumvent the solubility problems,
including the use of organic cosolvents, surfactants, and
hydrophilic auxiliaries.3
(
4) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
b) Asymmetric Organocatalysis; Berkessel, A., Gr o¨ ger, H., Eds.; Wiley-
(
So far the field of enantioselective organocatalysis in water
has afforded even more unsatisfactory results. In the past
few years a number of chemically robust organocatalysts
have become available, their application encompassing many
VCH: Weinheim, 2005. (c) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem.
ReV. 2003, 103, 3401.
(
5) (a) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 7386.
(b) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun. 2002, 3024.
(
(
c) Chimni, S. S.; Mahajan, D. Tetrahedron: Asymmetry 2006, 17, 2108.
d) Peng, Y.-Y.; Ding, Q.-P.; Li, Z.; Wang, P. G.; Cheng, J.-P. Tetrahedron
Lett. 2003, 44, 3871.
†
Dedicated to Prof. Achille Umani-Ronchi on his 70th birthday.
Dipartimento di Chimica Organica e Industriale.
Istituto di Chimica Organica.
(6) (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka,
F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734. (b) Mase, N.;
Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2006, 128, 4966.
(7) (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,
T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Hayashi, Aratake,
S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed.
2006, 45, 5527.
‡
§
(
1) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
Profesional: London, 1998. (b) Ribe S.; Wipf, P. Chem. Commun. 2001,
99.
&
2
(
2) Lindstr o¨ m, U. M. Chem. ReV. 2002, 102, 2751.
(3) Li, C.-J. Chem. ReV. 2005, 105, 3095.
1
0.1021/ol070002p CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/27/2007

8
9
were described, promoted by tryptophan, small peptides,
pyrrolidine-based catalysts,10 or proline-related systems.11
It should be noted that among all of the reported systems
only two organocatalysts really seem to work in the presence
6a,7b
of a large amount of water,
while other catalysts suffer
from different drawbacks: some of them work in mixed
9
,11b
aqueous organic solvent
or require the use of surfac-
tants,9 and others are supported11a or dendritic systems
,10
11c
whose preparation needs chemical manipulation. Often a
large excess of ketone is employed,7
a,8,10,11b,c
and the catalysts
perform in what, even if is defined as an aqueous medium,
really is a wet organic system.12
The development of chiral organic molecules able to
catalyze stereoselective reactions in pure water is the true
challenge. We wish to report here that 1,1′-binaphthyl-2,2′-
diamine-based (S)-prolinamides in combination with a proper
additive are efficient catalysts for direct aldol condensation
in the presence of a large amount of water, by employing a
small excess of ketone; the system has shown good generality
and is active enough to promote the reaction also of less
reactive aldehydes.13
Figure 1. Proline-based catalysts 1-7.
14
15
Recently we and others have reported the synthesis of
new organocatalysts obtained by connecting the proline
moiety to a 1,1′-binaphthyl-2,2′-diamine scaffold, easily
prepared in a few steps from inexpensive, commercially
available, enantiopure materials.16
First the prolinamide derivatives were employed in the
test aldol condensation between cyclohexanone and 4-nitro
benzaldehyde (Scheme 1, X ) NO ). By working in a 1:1
2
2 1
Differently functionalized C - and C -symmetric binaph-
thyl-2,2′-diamine-based (S)-prolinamides were prepared and
tested as catalysts (Figure 1). Enantiomerically pure com-
pounds 1-5 were synthesized according to the published
Scheme 1. Aldol Reaction of Cyclohexanone with 4-Nitro
Benzaldehyde in Water
14
procedure. Starting from the mono N-acetyl (R)-binaphthyl
diamine, catalyst 6 was synthesized in only four steps and
75% overall yield.
In order to compare the activity in water of binaphthyl
versus biphenyl-based catalytic systems, enantiomerically
pure 7 was also prepared in 51% overall yield.
water/cyclohexanone mixture, both C
2
-symmetric catalysts
1
and 2 afforded the product in quantitative yields and high,
comparable stereo- and enantioselectivities (entries 1 and 3
of Table 1). However by running the reaction in the presence
of a large amount of water (0.8 mL of water for 0.06 mL of
cyclohexanone and 0.03 g of aldehyde) the (S)-binaphthyl-
derived catalyst 2 proved to be superior to catalyst 1 in terms
of enantioselectivity (entries 2 and 4, 95% vs 69% ee). After
only 12 h at 2 °C, catalyst 2 promoted the aldol condensation
in 87% yield, 95/5 anti/syn ratio, and 93% ee for the anti
isomer (entry 5). Even at room temperature the product was
obtained with high enantioselectivity (91%), although with
lower diastereocontrol (anti/syn 80/20, entry 6).
(
(
8) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801.
9) Dziedzic, P.; Zou, W.; Hafren, J.; Cordova, A. Org. Biol. Chem. 2006,
4
, 38.
(10) Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun. 2006,
3
687.
(11) (a) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006,
8
2
8
, 4417. (b) Guillena, G.; Hita, M.; Najera, C. Tetrahedron: Asymmetry
006, 17, 1493. (c) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006,
, 4653.
(12) For a very interesting discussion of enantioselective organocatalysis
“
in water” or “in the presence of water”, 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.
13) We agree with Prof. Janda‘s opinion1 that so far no organic catalyst
2a
(
may be considered really working “in water”, since all of the organocatalysts
developed are insoluble in water. We also agree with Prof. Hayashi1 in
defining “in the presence of water” as a more appropriate expression for
reactions described in refs 6 and 7. However, it must be noted once again
that the catalysts of refs 6 and 7b are the only ones working in the presence
of a large excess of water, while this is not true in the other systems.
2b
1
The C -symmetric catalysts were also tested in the same
reaction conditions. Whereas all compounds 3-5 catalyzed
the aldol condensation in comparable enantioselectivities,
only slightly inferior to those obtained with catalyst 2, they
gave different results in terms of chemical activity. Mono
N,N-dimethyl (R)-binaphthyl-derived catalyst 3 afforded the
product in 100% yield, whereas the analogous (S)-binaphthyl-
based catalyst 4 and the mono N-acetyl derivative 5 promoted
the reaction in low yields (entries 7-9). Catalyst 6 seems to
behave not very differently from catalyst 3 in the diastereo-
(
14) Guizzetti, S.; Benaglia, M.; Pignataro, L.; Puglisi, A. Tetrahedron:
Asymmetry 2006, 17, 2754.
15) (a) Guillena, G.; Hita, M.; Najera, C. Tetrahedron: Asymmetry 2006,
(
1
2
1
7, 729. (b) Guillena, G.; Hita, M.; Najera, C. Tetrahedron: Asymmetry
006, 17, 1027. (c) Gryko, D.; Kowalczyk, B.; Zawadzki, L. Synlett 2006,
059.
(
16) For other organocatalysts prepared according to these principles,
see: Pignataro, L.; Benaglia, M.; Annunziata, R.; Cinquini, M.; Cozzi, F.
J. Org. Chem. 2006, 71, 1458.
1248
Org. Lett., Vol. 9, No. 7, 2007

allowed the yield of the process to improve dramatically.17
Organocatalyst 2 in the presence of benzoic acid promoted
the reaction in 71% yield and 73% ee (entry 2). The use of
both enantiomers of malic acid allowed further increase in
the enantioselectivity of the process but brought to the
product the same level (and the same sense) of enantiocontrol
Table 1. Aldol Reaction of Cyclohexanone with 4-Nitro
Benzaldehyde in Water (Scheme 1, X ) NO )
2
a
b
drc
d
entry
time (h)
catalyst
yield (%)
ee (%)
1e
2
3
60
60
60
60
12
12
12
12
12
12
12
1
1
2
2
2
2
3
4
5
6
7
100
94
100
90
88/12
88/12
95/5
92/8
95/5
80/20
90/10
93/7
99/1
93/7
88
69
92
95
93
91
87
89
84
67
63
(entries 3 and 4). A further improvement came when lauric
e
acid was used as additive (85% yield, 96/4 anti/syn ratio,
and 89% ee, entry 5). Along this line best results were
obtained with stearic acid as additive, which afforded the
product in 80% yield basically as a single anti isomer in
95% ee (entry 6).
4
5
6
87
f
100
100
47
21
44
7
8
9
1
The C -symmetric catalyst 5 promoted the reaction in
1
1
0
1
lower yields but comparable, very high stereo- and enantio-
selectivity, suggesting that chemical activity would depend
only on the number of catalytic sites present in the molecule,
such as the number of proline residues. The catalyst 3
afforded the product in both lower yield and stereoselectivity
compared with 2. The use of long alkyl chains at the nitrogen,
as in catalyst 6, brought better yields but even worse
enantioselectivities (entries 11 and 12 vs entries 7 and 8).
Finally also in the additive-assisted reaction in water, 7
afforded lower stereo- and enantiocontrol and dramatically
lower yield (entry 13, Table 2).
85
84/16
a
Reaction conditions: 0.8 mL of H2O, 0.6 mmol of ketone, 0.2 mmol
b
of aldehyde, 0.02 mmol of catalyst, 2 °C. Yields determined after
chromatographic purification. Diastereomeric excess determined by NMR.
Enantiomeric excess determined by HPLC (Chiracel OJ-H). Reaction
run in 1/1 ketone/H2O mixture. Reaction run at 25 °C.
c
d
e
f
control of the reaction but gave the product with diminished
enantioselection (entry 10).
Finally the biphenyl-based catalyst 7 promoted the reaction
in good yields but lower diastereoselectivity and especially
lower enantioselectivity compared to catalyst 2 (entry 11).
These results seem a clear indication that the identification
of the matching configurations of the stereogenic elements
in the molecule is not straightforward, but the stereogenic
axis of the binaphthyl diamine plays an important role in
helping to stereocontrol the condensation.1
Noteworthy catalysts type 2 seem to perform better in
1
4
water than in organic solvent; our working hypothesis is
that the binaphthyl moiety may build a sort of hydrophobic
pocket where the reaction takes place. Water would play a
decisive role in keeping the reactants and the catalyst in close
contact. In this picture the presence of long-chain carboxylic
acids should contribute to the construction of a lipophilic
cavity surrounded by massive bulk water.
4,15c
When catalyst 2 was employed in the condensation in
water of cyclohexanone with a nonactivated aldehyde, such
as benzaldehyde, the product was obtained in very low yield
The use of catalyst 2 in the presence of an acid additive
was extended to other aldehydic substrates (Scheme 2). In
(entry 1, Table 2). However, the use of an acidic additive
Scheme 2. Enantioselective Aldol Reactions of
Cyclohexanone in Water Promoted by Catalyst 2
Table 2. Aldol Reaction of Cyclohexanone with Benzaldehyde
in Water (Scheme 1, X ) H)a
time
yieldb
(%)
eed
drc (%)
entry (h) catalyst
additive
1
2
3
4
5
6
7
8
9
1
1
1
1
90
12
12
12
12
12
12
12
12
12
12
12
12
2
2
2
2
2
2
3
3
5
5
6
6
7
15 nd
71 86/14 73
nd
PhCO2H
the case of reactive aldehydes the addition of an acid caused
an acceleration of the reaction without any detriment to the
enantioselectivity of the process (Table 3). For example, the
condensation of 4-nitro benzaldehyde without any additive
afforded after 6 h the product in 45% yield, but in the
presence of benzoic acid after only 2 h the reaction was
complete with 91% ee. Also with 2-chloro benzaldehyde in
the presence of stearic acid the reaction was complete after
only 12 h with 87% ee. With pentafluorobenzaldehyde the
use of stearic acid improved the enantioselectivity up to 65%
(+)-PhCH-(OH)-CO2H
(-)-PhCH-(OH)-CO2H
C11H23CO2H
C17H35CO2H
C11H23CO2H
C17H35CO2H
PhCO2H
C17H35CO2H
PhCO2H
C17H35CO2H
C17H35CO2H
68 95/5
65 96/4
85 96/4
80 99/1
67 99/1
77 97/3
30 99/1
40 99/1
84
87
89
93
83
81
95
95
0
1
2
3
100 85/15 60
100 90/10 76
28 96/4
83
(entries 6 and 7). The presence of stearic acid successfully
a
Reaction conditions: 0.8 mL of H2O, 0.6 mmol of ketone, 0.2 mmol
promoted the condensation even of a deactivated aldehyde,
such 4-methoxy benzaldehyde (87% ee for the syn isomer).
b
of aldehyde, 0.02 mmol of catalyst, 0.04 mmol of additive, 2 °C. Yields
determined after chromatographic purification. Diastereomeric excess
determined by NMR. Enantiomeric excess determined by HPLC (Chiracel
c
d
OD).
(17) The use of acids as additive has been already reported; see refs 14
and 11b and citations within.
Org. Lett., Vol. 9, No. 7, 2007
1249

Table 3. Aldol Reactions in Water Promoted by Catalyst 2a
Table 4. Aldol Reactions in Water Promoted by Catalyst 2a
b
rrc
d
time
(h)
yieldb
(%)
eed
(%)
entry time (h)
additive
R
yield (%)
ee (%)
entry
additive
R
drc
1
2
3
4
5
72
12
12
12
12
C5H11
61
61
90
100
100
99/1
91/9
70/30
88/12
77
91
95
73
58
1
2
3
4
5
6
7
8
12
6
2
72
12
72
12
12
12
4-NO2Ph
4-NO2Ph
4-NO2Ph
2-ClPh
87
45
100
100
100
35
37
80
57
95/5
95/5
92/8
90/10
97/3
98/2
99/1
99/1
50/50
93
91
91
87
87
53
65
93
87
C17H35CO2H C5H11
C17H35CO2H CH3
C17H35CO2H CH3
e
f
PhCOOH
e
C17H35CO2H H
C17H35CO2H 2-ClPh
F5C6
C17H35CO2H
C17H35CO2H Ph
C17H35CO2H 4-OMePh
a
Reaction conditions: 0.8 mL of H2O, 0.6 mmol of ketone, 0.2 mmol
of aldehyde, 0.02 mmol of catalyst, 0.04 mmol of additive, 12 h, 2 °C.
Yields determined after chromatographic purification. Regioisomeric ratio
determined by NMR. Enantiomeric excess determined by chiral HPLC.
b
c
F5C6
d
e
f
e
Reaction run in 1:1 ketone/H2O mixture. Reaction run in only ketone.
9
a
Reaction conditions: 0.8 mL of H2O, 0.6 mmol of ketone, 0.2 mmol
of aldehyde, 0.02 mmol of catalyst, 0.04 mmol of additive, 12 h, 2 °C.
b
c
Yields determined after chromatographic purification. Diastereomeric
between cyclohexanone and benzaldehyde catalyzed by 2
and stearic acid. The “heterogeneous” nature of the reaction
medium, with the organocatalyst being mostly not soluble
in both water and pentane, might make the recovery of the
catalytic species quite troublesome. At the end of the reaction
pentane was added and the biphasic system was separated;
to the recovered “suspension” in aqueous phase, new reagents
d
excess determined by NMR. Enantiomeric excess determined by chiral
e
HPLC. Reaction run at 25 °C; ee % determined for syn isomer.
The combination of compound 2 and stearic acid proved
to be an efficient catalytic system also for the condensation
“
on water” of ketones other than cyclohexanone (Scheme
1
8
3). For example, the reaction of 4-nitrobenzaldehyde with
were added and the reaction was run again. The product
was obtained by simple evaporation of the pentane phase.
Following this procedure the recycle of the stearic acid/2
catalytic system provided the product in 45% yield, 98/2 anti/
syn ratio, and 93% ee (compared to 80% yield, 99/1 anti/
syn ratio, and 93% ee of the first cycle). Although the
methodology needs further work to be optimized, the recycle
Scheme 3. Aldol Reactions Promoted by Catalyst 2
1
9
the catalyst is feasible.
Acknowledgment. This work was supported by MIUR:
Nuovi metodi catalitici stereoselettivi e sintesi stereoselettiva
di molecole funzionali”.
2
-octanone without additive proceeded after 72 h in the usual
“
conditions in 61% yield and 77% ee for the anti isomer (entry
, Table 4), but in the presence of stearic acid after only 2
1
h the product was obtained with the same yield, 91/9 anti/
syn ratio, and 91% ee (entry 2). Also the reaction of methyl
ethyl ketone afforded the aldol product in 90% yield and
Supporting Information Available: Synthesis and char-
acterization of catalysts 6 and 7; general procedures for aldol
reactions and HPLC analysis details for aldol products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
9
1% enantioselectivity. It is worth mentioning that the
reaction promoted by the same catalytic system in only
-butanone afforded the product in high yields but lower
2
OL070002P
enantioselectivities, clearly pointing at a positive effect of
the aqueous environment in the condensation process (entries
(
18) Our system may be described as an “emulsion” rather than a biphasic
3
and 4).
6
system, like Barbas’ reactions. Please note once again in our conditions a
small excess of ketone is used and the ratio water/ketone is almost double
compared to both refs 6 and 7b.
The reaction with acetone afforded the product after 12 h
in 100% yield but lower enantioselection.
Finally, a preliminary experiment to recover and recycle
the catalytic system was attempted for the condensation
(19) For a proline-based recoverable organocatalytic system for reactions
in water, see ref 11c. For a general overview on recoverable chiral organic
catalysts, see ref 4c and Benaglia, M. New J. Chem. 2006, 30, 1525.
1250
Org. Lett., Vol. 9, No. 7, 2007