Organocatalytic asymmetric aldol reaction in the presence of water

Article abstract of DOI:10.1039/b703254d

Water was found to be a suitable solvent for the l-prolinethioamide catalysed aldol reaction of various cyclic ketones with aromatic aldehydes. Treatment of 4-nitrobenzaldehyde with as little as 1.2 equiv. of cyclohexanone in the presence of the protonate

Full text of DOI:10.1039/b703254d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalytic asymmetric aldol reaction in the presence of water
Dorota Gryko* and Wojciech J. Saletra
Received 5th March 2007, Accepted 2nd May 2007
First published as an Advance Article on the web 4th June 2007
DOI: 10.1039/b703254d
Water was found to be a suitable solvent for the L-prolinethioamide catalysed aldol reaction of various
cyclic ketones with aromatic aldehydes. Treatment of 4-nitrobenzaldehyde with as little as 1.2 equiv. of
cyclohexanone in the presence of the protonated catalyst 1–TFA, afforded aldol products in high yields
(
up to 97%) with high diastereo- and enantioselectivity (up to >5 : 95 dr and 98% ee). The use of a high
excess of ketone was avoided by conducting the aldol addition in the presence of water. Furthermore,
different ‘salting-out’ and ‘salting-in’ salts were investigated and it was proven that the rate of
acceleration and the stereochemical outcome of the reaction are affected by hydrophobic aggregation.
Scope and limitation studies revealed that electron deficient aldehydes afforded aldol products with
high stereoselectivity in the presence of 1–Cl
2
CHCO H. It was shown that various cyclic ketones, under
2
the conditions found, gave aldol products with fair yields, even if they are used in substoichiometric
amounts (1.2 to 2.0 equiv.).
Introduction
and those in which it is used as a main phase (on water). The
term ‘a reaction in water’ has been restricted to fully homogenous
conditions.
Water is the most abundant solvent in Nature but organic chemists
have neglected its use for a long time. In 2002, Lindstr o¨ m, in
his review, wrote: ‘this article will serve to rectify some of the
misconceptions that might persist with many chemists regarding
the inadequacy of water as solvent for organic reactions’.
However, water is a desirable solvent for chemical reactions mainly
because of cost, safety, and environmental concerns. In addition,
the performance of organic reactions in aqueous conditions might
lead to different results as compared with those obtained in purely
organic solvents, regardless of whether the reactants are soluble
To date, aldol reactions in the presence of water have afforded
aldol products with high diastereoselectivity and enantioselec-
tivity; unfortunately, in most cases, a large excess of ketone is
1
18,21–29
17
needed.
In two notable examples, the laboratories of Barbas
25
and Zhao used respectively only 2 or 3 equiv. of cyclohexanone
but 10 mol% of catalyst was employed. Thus, the development of
efficient organocatalysts for the asymmetric aldol reaction, both
in water and in the presence of water, still remains a hot area of
research.
2,3
4,5
or not in water.
To develop organic reactions which are water-compatible is a
great challenge since water breaks the hydrogen bonds that are
Results and discussion
6,7
crucial in many transition states. Despite this fact, in recent years
water has attracted much attention as a solvent with important
New organocatalysts for the direct organocatalysed aldol reaction
have been attracting much attention since the seminal discovery
by List, Lerner and Barbas. We have contributed to this field by
showing that simple L-prolinethioamides can effectively catalyse
4,8,9
advances being made. However, in many cases, transition–metal
complexes have been employed. Only within the last few years has
1
0
10–13
the organocatalysed direct aldol reaction been rediscovered.
30–32
the reaction of acetone with various aromatic aldehydes.
Later,
Although proline can catalyse direct aldol reactions in organic
solvents with high enantioselectivity, it leads to racemates in
it was proved that the TFA-assisted aldol reaction proceeded
through enamine-iminium catalysis. Since Janda et al. wrote that
the addition of TFA (or any acid) to the reaction of cyclohexanone
with 4-nitrobenzaldehyde in the presence of a chiral diamine
favours the formation of micelles by increasing the amphiphilic
14–16
water.
Therefore, given the synthetic utility of the asymmetric
aldol reaction, there is a growing search for an organic catalyst
that can effectively promote this reaction in water. Recently
Barbas’s and Hayashi’s groups have independently reported highly
19
17,18
character of the catalyst, we envisaged that our catalytic system
of L-prolinethioamide and TFA could be used in the presence of
water.
stereoselective aldol reactions ‘in water’ or ‘aqueous’.
Since
there has been some confusion concerning the terminology or
19
whether these reactions are ‘really wet’, Hayashi has proposed to
use the term ‘a reaction in the presence of water’ for reactions that
proceed in a concentrated organic phase with water being present
as a second phase, which influences the reaction in the organic
To verify this hypothesis, we started from the conditions
17
described by Barbas et al. A reaction of 4-nitrobenzaldehyde
3) with cyclohexanone (2) catalysed by 1–TFA in the presence
(
20
of water gave product 4 in 96% yield with high diastereo- and
enantioselectivity (Scheme 1; Table 1, entry 1). When the catalyst
loading was lowered to 5%, the yield did not change (entry 2).
However, a further decrease in the amount of catalyst or ketone
used led to a decrease in the yield, but did not affect the degree
of diastereo- and enantioselectivity (entries 3 and 4). On the other
phase. Here we would like to point out that there is a huge
difference between reactions in which water is used as an additive
Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka
4
8
4/52, Warsaw, Poland. E-mail: dgryko@icho.edu.pl; Fax: +48 22 632 66
1; Tel: +48 22 343 21 29
2
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a
Table 1 The aldol reaction of cyclohexanone (2) with 4-nitrobenzaldehyde (3) catalysed by 1–TFA in the presence of water
b
c
d
Entry
Catalyst (mol%)
Ketone (mmol)
Yield (%)
Ratio syn–anti
Ee of 4-anti (%)
1
2
3
4
10
5
2.5
5
2
2
2
96
96
72
23
82
10 : 90
5 : 95
5 : 95
5 : 95
13 : 77
94
94
90
89
86
1.2
Neat
32
5
10
a
b
c
1
All reactions were run in the presence of 1–TFA on 1 mmol scale in 2 ml of water at rt for 18 h. Isolated yields. Determined by H NMR spectroscopy
d
of the crude reaction mixture. Determined by chiral HPLC using an ADH-column.
5
types of reactions are called ‘on water’. However, it is still not
clear whether reactions ‘on water’ are influenced by hydrophobic
33,34
aggregation or by other effects.
To clarify whether the hydrophobic effect plays a crucial role in
the L-prolinethioamide catalysed aldol reaction, experiments with
35
‘
salting-out’ and ‘salting-in’ salts were conducted. ‘Salting-out’
salts increase the hydrophobic effect, by electrostriction of water,
which decreases the solubility of hydrocarbons and thus promotes
their association. Conversely, ‘salting-in’ decreases the association
of hydrocarbon residues in water. Takabe and Barbas et al., who
used brine as the aqueous medium in a direct Michael reaction,
for the first time added NaCl to an organocatalysed reaction in the
36
presence of water. The beneficial influence of brine over water
was explained only on the basis of ionic complexation and the
‘
salting-out’ effect was not taken into consideration.
In our case, the use of brine as the reaction medium for the aldol
Scheme 1 The model aldol reaction of 4-nitrobenzaldehyde (2) with
cyclohexanone (3) catalysed by 1–TFA in the presence of water.
reaction of cyclohexanone (2) with 3 catalysed by 1–TFA, allowed
us to decrease the amount of the ketone 2 to as little as 1.2 equiv.
per 1 mmol of 3 (Table 2, entry 1). Reactions in the presence of less
saturated NaCl aqueous solutions gave the same stereochemical
results, but lower yields (entries 3–5). Furthermore, other ‘salting-
out’ salts were tested and the results are presented in Table 2
(entries 6–12). The reaction in the presence of an aqueous solution
hand, when cyclohexanone (2) was used as a solvent and as a
donor, the reaction afforded aldol product 4 with lower yield and
decreased diastereo- and enantioselectivity (entry 5). Thus, the role
of water in the studied reaction is not only as the reaction medium,
but it also influences the reaction rate and stereoselectivity. A
similar phenomenon was observed by Sharpless et al. and these
of NH
4
Cl afforded only 45% of aldol product 4, presumably
a
Table 2 ‘Salting-out’ and ‘salting-in’ salts as additives for the aldol reaction in the presence of water
b
c
d
Entry
Salt
Catalyst (mol%)
Yield of 4 (%)
Ratio syn–anti
Ee of 4-anti
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
NaCl (sat)
NaCl (sat)
NaCl (350 mg)e
NaCl (350 mg)
NaCl (175 mg)
LiCl (sat)
5
2.5
5
5
5
5
5
5
5
5
5
5
5
90
56
90
33
66
24
86
24
45
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
15 : 85
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
nd
nd
nd
nd
10 : 90
10 : 90
92
87
90
95
91
85
94
93
93
91
93
nd
nd
nd
nd
85%
rac
KCl (sat)
CaCl
NH Cl (sat))
Na
MgSO
LiClO
2
(sat)
4
1
1
1
1
1
1
1
1
2
SO
4
4
(sat
(sat)
(sat)
93
90
4
Traces
Traces
Traces
Traces
100
51
Guanidine chloride (sat)
Urea (sat)
5
Phosphate bufferf
10
20
20
Phosphate buffer
g
Phosphate buffer
a
Reactions were carried out using 1.2 mmol of 2 for 1 mmol of aldehyde 3 in the presence of 1–TFA (indicated in the Table) in 2 ml of water at rt for
b
c
1
d
e
1
4
8 h. Isolated yields. Determined by H NMR analyses of the crude product. Determined by chiral-phase HPLC analyses. The reaction was run at
f g
◦
C. The reaction was run in phosphate buffer (pH = 7.2) for 2 days. Free base catalyst was used.
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37
because of different water–salt interactions as shown by Symons
entry 9). To support our hypothesis concerning the hydrophobic
A range of aromatic aldehydes, 5–16, was explored and the
results are summarised in Table 4.
(
effect, ‘salting-in’ materials such as guanidinium chloride and
urea were tested in the model aldol reaction. Reactions in such
aqueous solutions led only to the recovery of the starting material
Regardless of the aldehyde used, high diastereo- and enantios-
electivity was observed, though the rate of the aldol reaction
strongly depended on the electrodeficiency of the substrate. In
most cases, 1.5 equiv., instead of 1.2 equiv., of cyclohexanone (2)
had to be used and/or longer reaction times were required at the
slight cost of diastereo- and enantioselectivity. Under the present
reaction conditions, less reactive aldehydes did not afford aldol
products with acceptable yields, although the stereoselectivity
remained at the same level, for example, see entry 16. Though
N a´ jera et al. found that for BINAM-prolineamides, an excess of
3
(entries 13 and 14).
On the other hand, the rate acceleration may be attributed to hy-
drogen bonding interactions. Symons has pointed out the changes
in water properties that occur when different types of anions are
37
added. Small coordinating anions bind to water protons and thus
decrease the ability of water to hydrogen bond other substrates.
35
Following Breslow and Rizzo’s studies, we also considered the
hydrogen bonding explanation for the rate acceleration, reactions
22
acid had beneficial effects on the yield and enantioselectivity, in
our case, the use of higher amounts of acid did not improve the
catalytic activity of our system, and resulted in a decrease of the
stereoselectivity (entry 17).
in the presence of LiCl and LiClO
bonds influence the reaction, LiClO
4
were conducted. If hydrogen
should speed up the reaction
4
more than LiCl does; the salting-in explanation would predict the
opposite effect. We found that the direct aldol reaction catalysed by
Despite the great variety of aldol acceptors that have been
used in direct aldol reactions under water conditions, the range
of donors has remained narrow. Recently, Xiao et al. have
reported the highly diastereo- and enantioselective aldol reactions
1–TFA in the presence of a saturated aqueous solution of LiClO
4
was indeed slower as compared with the one conducted in the
presence of a LiCl solution (compare entries 6 and 12). These data
confirm the idea that hydrophobic packing effects contribute to
the L-prolinethioamide catalysed aldol reaction in the presence
of water. Finally, since no small molecule catalysts have provided
40
of heterocyclic ketones with aldehydes in organic solvent. It
was shown that heterocyclic ketones such as 4-thianone, 4-
Boc piperidinone and tetrahydro-4H-pyran-4-one afforded aldol
products with excellent yields and stereoselectivities, though an
excess of ketone was necessary. Given the fact that these donors
are not the cheapest ones and that they must be separated from
the aldol product (that is not an easy task), it would be beneficial
if the amount of ketone could be stoichiometric or at least
substoichiometric. In a very elegant report, Pihko et al. described
conditions for the stoichiometric aldol reaction of tetrahydro-
4H-thiopyran-4-one with benzaldehyde, however the reaction was
38,39
relevant enantioselectivity in aqueous buffered solutions,
have checked our 1–TFA system using those conditions. Using
0 mol% of the catalyst (1–TFA), the model aldol reaction in
phosphate buffer (pH = 7.2) afforded exclusively 3-hydroxy ketone
with high diastereoselectivity and 85% ee (entry 16). The reaction
we
2
4
without TFA led to a decrease in the enantiomeric enrichment, the
addition of an acid favours the formation of micelles increasing
the amphiphilic character of the catalyst (entry 17).
41
Following our recent publication on the influence of an acid
on the aldol reaction, we thought it worthy to study whether
the nature of the acid is also an important factor for this
sluggish.
We studied the use of various cyclic 30–32 and heterocyclic 33–
35 ketones for the aldol reaction in the presence of water and the
results are summarized in Table 5. 4-Methylcyclohexanone (30)
and monoprotected cyclohexane-dione 31 afforded almost exclu-
sively optically pure anti-adducts 36 and 37 respectively (entries 1
and 2). The reaction of cyclopentanone (32) with 3 gave a mixture
of syn and anti product 38 with moderate enantioselectivity, which
could be attributed to the higher miscibility of 32 with water
(entry 3). For heterocyclic ketones 33–35, new reaction conditions
were defined. Tetrahydro-4H-thiopyran-4-one (33) and 1-Boc-4-
piperidone (34) smoothly reacted with 4-nitrobenzaldehyde (3)
leading to anti-aldol products 39 and 40 respectively with fair
diastereo- and enantioselectivity (entries 7 and 9). Since both
32
transformation conducted in the presence of water.
Surprisingly, the reaction of cyclohexanone (2) with 4-
nitrobenzaldehyde (3) by 1–HCl in the presence of brine gave aldol
product 4, contrary to the reaction of acetone with 3 (Table 3,
entry 1). However, the best results were obtained with the use of
1–Cl
2
CHCO H; the catalyst loading could be lowered to as little
2
as 2.5% mol (entry 5). A further decrease in the amount of the
catalyst led to a decrease in the reaction rate which subsequently
lowered the enantiomeric purity of the anti-aldol 4 (entry 6) (the
longer the reaction time, the lower the enantiomeric purity of 4-
anti).
a
Table 3 The influence of an acid additive on the model aldol reaction
b
c
d
Entry
Acid
Catalyst (mol%)
Reaction time/h
Yield (%)
Ratio syn–anti
Ee of 4-anti
1
2
3
4
5
6
HCl
5
5
5
5
2.5
1.25
16
16
16
6
28
60
50
92
97
64
97
72
10 : 90
19 : 81
7 : 93
5 : 95
7 : 93
7 : 93
85
78
92
94
93
79
4-Methylbenzoic acid
Cl
2
Cl
2
Cl
2
Cl
2
CHCO
CHCO
CHCO
CHCO
2
2
2
2
H
H
H
H
a
b
Reactions were carried out using 1.2 mmol of 2 for 1 mmol of aldehyde 3 in the presence of 1–acid (indicated in the Table) in 2 ml of brine at rt. Isolated
c
1
d
yields. Determined by H NMR analyses of the crude product. Determined by chiral-phase HPLC analyses.
2
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a
Table 4 Scope and limitation studies
b
c
d
Entry Aldehyde
Catalyst (mol%) Amount of 2 (equiv.) Reaction time/h
Yield (%)
Ration syn–anti
Ee of anti
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
2-NO
2-NO
3-NO
3-NO
4-CNC
4-CNC
2-ClC
3-ClC
4-ClC
4-ClC
2
2
2
2
C
C
C
C
6
6
6
6
H
H
H
H
4
4
4
4
(5)
5
5
5
5
5
5
5
5
5
5
5
5
5
2.5
5
5
10
1.2
1.5
1.2
1.5
1.2
1.5
1.5
1.5
1.5
3.0
3.0
1.5
1.5
1.2
1.5
1.5
1.5
48
16
48
16
16
16
16
48
48
48
18
48
16
16
48
48
48
91
90
72
80
87
96
80
82
48
58
25
57
86
82
86
23
23
(17)
(17)
(18)
(18)
(19)
(19)
(20)
(21)
(22)
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
12 : 88
7 : 93
9 : 91
4 : 96
> 5 : 95
9 : 91
97
97
94
96
93
93
96
93
92
96
91
93
97
98
98
83
68
(5)
(6)
(6)
6
H
H
4
(7)
6
4
(7)
6
6
6
6
H
H
H
H
4
4
4
4
(8)
9 : 91
(9)
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
> 5 : 95
(10)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(16)
1
1
1
1
1
1
1
1
4-FC
6
H
4
4-BrC
6
H
4
F
5
C
6
4-CF
4-CO
3
C
6
H
4
2
6 4
MeC H
2-Naphthyl
2-Naphthyl
e
a
b
c
1
d
Reactions were run on 1 mmol scale in 2 ml of water at rt. Isolated yields. Determined by H NMR analyses of the crude product. Determined by
e
2 2
chiral-phase HPLC analyses. Additional 10% of Cl CHCO H was used.
the ketones 33, 34 and the aldehyde 3 are water-insoluble solids,
contrary to 1–Cl CHCO H, the reactions were slower and 2 equiv.
catalysed aldol reaction in the presence of water, one could even
state that the reactions were run at hydrophobic control.
2
2
of ketone had to be used. Thus, the reactions may be regarded as
biphasic.
Experimental
Surprisingly, with liquid tetrahydro-4H-pyran-4-one (35), the
aldol reaction afforded product 41 with a moderate yield. From
this, one could conclude that the miscibility is not the most
important factor influencing the studied reaction (entry 11).
Though the stereochemical results for the aldol reaction of
heterocyclic ketones with aldehydes reported by Xiao are superior
to those presented in the current paper, our reaction conditions
offer several advantages. From a preparative point of view, the
ability to conduct the reactions ‘on water’ in substoichiometric
conditions holds significant advantages. Further studies focusing
on the improvement of the catalyst structure are currently under
investigation.
General
All chemicals were used as received unless otherwise noted.
Reagent grade solvents (CH
use. All reported H NMR spectra were collected on a Bruker
spectrometer at 500 ( H NMR) and 125 ( C NMR) MHz.
2
Cl
2
, hexanes) were distilled prior to
1
1
13
Chemical shifts are reported as d values relative to TMS signal
1
13
defined at d = 0.00 ( H NMR) or d = 0.0 ( C NMR). IR spectra
were obtained on a Perkin-Elmer 1640 FTIR unit. Mass spectra
were obtained on a Mariner PerSeptive Biosystem instrument
using the ESI technique. Chromatography was performed on silica
gel (Kieselgel 60, 70–230 mesh). Melting points were determined
using a Kofler hot-stage apparatus and are uncorrected. The ee
values were determined by HPLC using a Daicel OD–H, AS–H
or AD–H column and the configuration was assigned as R by
comparison of the retention time with the reported data.
Conclusions
In conclusion, we have shown that water is a suitable solvent for
the direct asymmetric aldol reaction of various cyclic ketones with
aromatic aldehydes in the presence of L-prolinethioamide 1 and
an acid. The use of water effectively enhanced the activity of the
catalyst, allowing it to be used in only 1.3 mol%. At the same time,
General procedure for the 1–acid catalysed aldol reaction in the
presence of water
1
.2 equiv. of ketone per 1 mmol of aldehyde was enough to obtain
a high yield within a reasonable period of time.
To a solution of 1–Cl
2
CHCO H in water (2 mL), cyclohexanone (2)
2
Furthermore, our studies with ‘salting-out’ and ‘salting-in’
materials showed that the hydrophobic effect plays a crucial role in
the aldol reaction conducted in the presence of water. Experiments
was added, followed by 4-nitrobenzaldehyde (3) (151 mg, 1 mmol).
The reaction mixture was vigorously stirred for the indicated
period of time. Amounts of 1–acid and of 2 and reaction times
are specified in Tables 4 and 5. After the removal of water, the
with the addition of LiClO and LiCl confirm the idea that
4
hydrophobic packing effects contribute to the L-prolinethioamide
resulting solid was dissolved in CH
2
Cl
2
and the solution was
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a
Table 5 Investigation of the ketone scope
Amount of
ketone (equiv.)
Catalyst
(mol%)
b
c
d
Entry
Ketone
Time/h
Yield (%)
Ratio syn–anti
Ee of anti
1
2
1.5
1.5
5
5
16
36
87
97
> 5 : 95
> 5 : 95
97
92
e
(
30)
(36)
3
4
(31)
1.5
1.5
10
5
36
16
96
72
(37)
> 5 : 95
95
87
(32)
(33)
(38)
(39)
45 : 55
5
6
7
1.2
2.0
2.0
10
10
20
16
36
36
32
69
85
> 5 : 95
> 5 : 95
> 5 : 95
97
95
94
8
9
1.5
2.0
10
10
36
36
65
96
11 : 89
40 : 60
81
91
(
(
34)
35)
(40)
(41)
1
1
0
1
2.0
2.0
10
20
36
36
43
54
40 : 60
38 : 62
86
88
a
b
c
1
d
Reactions were run on 1 mmol scale in 2 ml of brine at rt. Isolated yields. Determined by H NMR analyses of the crude product. Determined by
e
chiral-phase HPLC analyses. Dr with respect to the methyl group was > 5 : 95.
1
dried over Na
2
SO
4
. Diastereoselectivity was determined by H
Acknowledgements
NMR of the crude reaction mixture. Purification using column
chromatography (hexanes–AcOEt, gradually) gave aldol product
. The enantiomeric excess of 4 was determined by chiral-phase
This work was supported by the Ministry of Sciences and Higher
Education, grant number 1T09A 083 30.
4
HPLC analysis.
Notes and references
(
S)-2-[(R)-Hydroxy(4-carboxymethylphenyl)methyl]cyclohexa-
none 27-anti. Purification using flash column chromatography
hexanes–AcOEt, gradually) gave title compound 27-anti (224 mg,
6%) as a white solid (found: C, 68.61; H, 7.08. C15 requires
1
2
3
U. M. Lindstr o¨ m, Chem. Rev., 2002, 102, 2751–2772.
Organic Synthesis in Water, ed. P. Grieco, Blackie, London, 1998.
C.-J. Li and T. H. Chan, Organic Reactions in Aqueous Media, Wiley,
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C.-J. Li, Chem. Rev., 2005, 3095–3165.
5 S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb and K. B.
(
8
H
18
O
4
◦
20
4
C, 68.89; H, 6.92%); mp 62–64 C; [a] = +23.8 (c = 1.0, CHCl
3
);
D
−
1
m
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