Dual stereocontrol in aldol reactions catalysed by hydroxyproline derivatives in the presence of a large amount of water

Article abstract of DOI:10.1016/j.tetasy.2016.08.009

Parameters influencing dual stereocontrol in aldol reactions of water miscible acetone with aromatic aldehydes in the presence of a large amount of water using hydroxyproline based catalysts were studied. Stereocontrol was achieved by changing the acidity and basicity of the reaction media by the addition of achiral salts in the presence of a single chiral catalyst. Under acidic conditions (NH₄Cl salt) the (R)-aldol product was formed in excess while basic aqueous media (carboxylate salts) led to the enrichment of the (S)-enantiomer. Reaction conditions under which the reaction is feasible were optimised and the effect of the structure of the hydroxyproline-based catalysts was investigated. The results show that the formation of a biphasic micellar system and the presence of an appropriate catalyst are both crucial for the reaction to occur. Although the catalyst structure influenced the formation and stabilisation of the micellar system to a large extent, its effect on the enantioselectivities were found to be less pronounced.

Full text of DOI:10.1016/j.tetasy.2016.08.009

Tetrahedron: Asymmetry 27 (2016) 936–942
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Dual stereocontrol in aldol reactions catalysed by hydroxyproline
derivatives in the presence of a large amount of water
a
b
András A. Gurka , Kornél Szori , Mihály Bartók a,b, Gábor London b,
⇑
}
a Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
b MTA-SZTE Stereochemistry Research Group, Dóm tér 8, H-6720 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Parameters influencing dual stereocontrol in aldol reactions of water miscible acetone with aromatic
aldehydes in the presence of a large amount of water using hydroxyproline based catalysts were studied.
Stereocontrol was achieved by changing the acidity and basicity of the reaction media by the addition of
achiral salts in the presence of a single chiral catalyst. Under acidic conditions (NH4Cl salt) the (R)-aldol
product was formed in excess while basic aqueous media (carboxylate salts) led to the enrichment of the
(S)-enantiomer. Reaction conditions under which the reaction is feasible were optimised and the effect of
the structure of the hydroxyproline-based catalysts was investigated. The results show that the formation
of a biphasic micellar system and the presence of an appropriate catalyst are both crucial for the reaction
to occur. Although the catalyst structure influenced the formation and stabilisation of the micellar system
to a large extent, its effect on the enantioselectivities were found to be less pronounced.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 21 June 2016
Accepted 2 August 2016
Available online 28 August 2016
1. Introduction
challenges.1–5,11,12 This field, however, strongly relies on accidental
findings as is often clear from papers reporting unexpected or unu-
Dual stereocontrol, that is, the access to both enantiomers of a
product without any direct modification of the chemical structure
of the chiral promoter,1–5 has gained importance as chirality has
become a major topic in drug design.6–8 Today it is clear that differ-
ent enantiomers of chiral drug molecules could have very distinct
effects in the interaction with their biological targets.8 As a
consequence, most of the newly introduced chiral drugs are single
enantiomers.6,7 Accessing both enantiomers of a molecule, how-
ever, is not always straightforward.
Traditionally, most of the asymmetric approaches to the syn-
thesis of enantiopure compounds are restricted to only one enan-
tiomer.9,10 This limitation could be overcome when both
enantiomers of the chiral promoter is available, for example, using
chiral catalysts from natural sources. In most of the cases, however,
a given enantiomer is produced with a well-designed synthetic
chiral catalyst, while obtaining the other enantiomer requires the
synthesis of the catalyst with opposite configuration. This latter
process could be laborious and expensive, thus, limiting the avail-
ability of both products. Using catalysts/ligands from a single chiral
source to access both enantiomers of a product in an enantiodiver-
gent fashion has become a major concept to tackle the above
sual inversions of configuration in a given reaction originating from
changes in reaction conditions.4
Among these reactions, the development of organocatalytic
examples would be of great importance, as they represent facile,
economic and reliable methodologies that are crucial for the syn-
thesis of pharmaceuticals.13–16 Asymmetric aldol chemistry, argu-
ably the most studied reaction within the framework of
enantioselective organocatalysis, has been shown to be a useful
tool in the synthesis of pharmaceutically relevant compounds.17
However, realizing dual stereocontrol in aldol reactions is cur-
rently a considerable challenge in asymmetric catalysis. This is
especially true for aldol reactions in the presence of a large amount
of water without using co-solvents and for water miscible ketones
such as acetone.18,19 There are only a limited number of examples
where both enantiomers could be prepared in aldol reactions of
acetone in general and in aqueous reactions in particular.20–27 This
lack of activity in the field is surprising, and in sharp contrast to the
research efforts towards environmentally benign asymmetric syn-
thesis in water.18,19,28–31 Nonetheless, a few of such reactions have
been reported in the literature. From the literature examples it is
clear, that the stereocontrol largely depends on the protonation
state of the amine-based catalyst20,21,23,25–27 that is especially well
studied in the case of proline.23,27,32 The most relevant examples of
proline-based dual stereocontrol21,23,27 is shown in Figure 1.
⇑
Corresponding author. Tel.: +36 62 544 279; fax: +36 62 544 200.
E-mail address: londong@chem.u-szeged.hu (G. London).
http://dx.doi.org/10.1016/j.tetasy.2016.08.009
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

A. A. Gurka et al. / Tetrahedron: Asymmetry 27 (2016) 936–942
937
(a) Li et al.21
Here we report a systematic study on the factors influencing the
catalysis in this reaction focusing on the formation and enantiose-
lectivity of the (S)-product that is the opposite of that accessible
O
OH
*
O
O
with L-proline-catalysis in organic solutions. We found a strong
H
dependence of the catalytic activity on the catalyst structure in
aqueous media in terms of conversion, selectivity and enantiose-
lectivity. Some of these features were also reflected in the results
obtained in organic solutions. The results represent important
design elements for further development of dual stereocontrol in
the presence of water.
acetone
O2N
O2N
L
-Pro: (R)-aldol (68% ee)
L
-Pro/γAl2O3: (S)-aldol (21% ee)
(b) Blackmond et al.23
2. Results and discussion
O
Cl
O
Cl
OH
*
O
It is known that in several organic reactions in aqueous media
the addition of inorganic salts as salting-out agents is beneficial
to promote the reactions.34–41 As we also found that the presence
of salt additives were crucial to the formation of a biphasic micellar
system in which the reaction occur, we explored their influence on
the outcome of the reaction (Table 1). In the case of using Na-car-
boxylates in the presence of catalyst 1, we found that the ee
increased slightly with the carbon chain length, however, NaOAc
was delivering the best results in terms of conversion and selectiv-
ity (Table 1, entries 2 and 5). Upon addition of polypropylene glycol
(PPG-425) to the reaction mixture (Table 1, entries 5–7), as an aid
for the formation of a biphasic system42,43 (polyethylene glycol
PEG-1000 has the same effect, too), the conversions and selectivi-
ties were increased and a further increase in the ee was found in
the case of Na-butyrate (Table 1, entry 7). It is noted, that the selec-
tivity of the reaction in each case was lowered only by the forma-
tion of the dehydration product.
H
CH2Cl2
L
-Pro: (R)-aldol (72% ee)
L
-Pro/DBU: (S)-aldol (24% ee)
(c) Breslow et al.27
O
OH
CH2O
water
HO
H
H
*
OH
O
L
L
-Pro/pH 2.9-4.2: (S)-aldol (20.4 0.3% ee)
-Pro/pH 6.6-7.6: (R)-aldol (2.0 0.5% ee)
Figure 1. Dual stereocontrol in proline-catalysed aldol reactions between acetone
and aromatic aldehydes (a, b) and in the presence of a large amount of water (c).
Table 1
The effect of sodium carboxylate salts on the reaction between acetone and
Recently, we have disclosed a catalytic system where dual
enantiocontrol could be realized in the reaction of acetone with
aromatic aldehydes in the presence of a large amount of water
with hydroxyproline derivative 1 as the single chiral source
(Fig. 2).33 The formation of the different enantiomers was depen-
dent on the nature of salt additives. Upon using NH4Cl, providing
an acidic aqueous solution, the (R)-product was formed that is
2-nitrobenzaldehyde catalysed by 1 in the presence of watera
Entry Salt additive [mmol] Conversion [%]b Selectivity [%]b,c ee [%]b
1
2
HCOONa (7.4)
NaOAc (6.1)
Na(C2H5COO)
Na(C3H7COO) (2.0)
NaOAc (6.1)
67
91
89
80
94
93
87
87
83
82
87
95
96
96
10 (S)
20 (S)
22 (S)
24 (S)
20 (S)
18 (S)
26 (S)
3d
4e
5f
6d,f
7f
the same as with L-Pro in organic media. The addition of NaOAc,
Na(C2H5COO)
Na(C3H7COO) (2.0)
providing a rather basic aqueous environment, resulted in the for-
mation of the opposite (S)-enantiomer. Importantly, we found that
the formation of a micellar biphasic system is essential for the
reactions to occur, thus the catalyst structure is crucial for stabilis-
ing such a system in order to achieve product formation and
enantioselectivity.
a
Reaction conditions: 0.5 mmol aldehyde, 2 mmol acetone, 30 mol % catalyst,
2 mL water, rt, 6 h.
b
Determined by chiral GC-FID analyses. (See also Section S1, ESI.)
Selectivity of the aldol product.
20 wt % aqueous solution of the salt was used.
Saturated solution was used (solubility: 0.1 g Na-butyrate/1 mL water at 20 °C).
c
d
e
f
0.95 mmol PPG-425 was used as additive.
O
OH
O
O
While the nature of the salt has some influence on the reaction
outcome, its amount is crucial for the reaction to occur (Table 2).
When lower amounts of salt (NaOAc) were used (0.075–0.3 mmol,
Table 2, entries 1–3) essentially no reaction took place. Increasing
the amount up to 6.1 mmol, however, resulted in an efficient
reaction. These results are pointing towards the role of NaOAc as
a salting-out additive that forces water miscible acetone to form
a heterogeneous organic phase (acetone/water interface), thus
allowing the reaction to take place. Furthermore, they confirm that
the polymeric surfactant (PPG-425, PEG-1000), although helps to
improve the results, without a sufficient amount of salt it has a
negligible effect due to the lack of micellar structure formation.
Catalyst 1 has a two-fold role in the system: It stabilises the form-
ing emulsion on one hand and catalysing the reaction within the
organic phase on the other.
H
*
water
NO2
NO2
1
/NH4Cl: (R)-aldol (58% ee)
1/NaOAc: (S)-aldol (22% ee)
O
COOH
O
NH
1
Figure 2. Dual stereocontrol in the aldol reaction of acetone and aromatic
aldehydes in the presence of a large amount of water (222 equiv) catalysed by 1.33

938
A. A. Gurka et al. / Tetrahedron: Asymmetry 27 (2016) 936–942
Table 2
Reaction time has influence only on the progress of the reaction
but not on the selectivity and enantioselectivity (Table 5). After 2 h
of reaction the selectivity and ee remained unchanged, while the
conversion increased up to 6 h where the reaction was complete.
The effect of the amount of NaOAc on the reaction between acetone and
2-nitrobenzaldehyde catalysed by 1 in the presence of watera
Entry
NaOAc [mmol]
Conversion [%]b
Selectivity [%]b,c
ee [%]b
1
2
3
4
0.075
0.15
0.3
2.4
6.1
3
5
6
64
92
91
81
81
83
75
83
96
83
80
18 (S)
10 (S)
7 (S)
16 (S)
22 (S)
20 (S)
20 (S)
Table 5
The effect of reaction time on the reaction between acetone and 2-nitrobenzaldehyde
catalysed by 1 in the presence of watera
5
6d
7d
6.1
12.2
Entry
Time [h]
Conversion [%]b
Selectivity [%]b,c
ee [%]b
1
2
3
2
4
6
72
84
94
94
93
95
20 (S)
20 (S)
20 (S)
a
Reaction conditions: 0.5 mmol aldehyde, 2 mmol acetone, 30 mol % catalyst,
0.48 mmol PEG-1000, 2 mL water, rt, 6 h.
b
Determined by chiral GC-FID analyses. (See also Section S1, ESI.)
Selectivity of the aldol product.
Reactions performed without PEG-1000 additive.
a
Reaction conditions: 0.5 mmol aldehyde, 2 mmol acetone, 6.1 mmol NaOAc,
0.95 mmol PPG-425, 2 mL water, rt.
c
d
b
Determined by chiral GC-FID analyses. (See also Section S1, ESI.)
Selectivity of the aldol product.
c
Changing the counter ion of the acetate salt from sodium to
other alkali metals, generally, had little influence on the reaction
outcome in terms of conversion and selectivity (Table 3, entries
1, 3 and 5). Selectivity values could be further increased by the
addition of PPG-425 (Table 3, entries 2, 4 and 7). Interestingly,
the additions of LiOAc resulted in comparably lower enantioselec-
tivities. Such effect of Li-salts on the stereochemistry has been
observed in related reactions.23,37 In contrast to alkali metal coun-
ter ions, the presence of tetrabutylammonium acetate was not
beneficial for the transformation. However, its combination with
PPG-425 led to a pronounced increase in conversion and a slight
increase in enantioselectivity (Table 3, entry 8 vs 9).
We synthesized a library of acyloxyprolines in order to establish
the relationship between catalyst structure and catalytic activity
and stereoselectivity of the reaction (Fig. 3). We used the structure
of catalyst 1 as a reference point. First, we examined the role of the
tert-butyl substituent on the benzoyloxy group of the molecule. For
this, we synthesized compound 2 having an n-hexyl chain instead
of the tBu and 3 that is lacking the alkyl chain in its structure. Both
transformations resulted in a less efficient catalyst. Compound 2
lost some activity in terms of conversion while the ee decreased
slightly. However, without the alkyl chain on the aromatic ring,
as is the case in 3, pronounced decrease was obtained in all values.
The 26% conversion in this case compared to the 91% for 1 and 71%
for 2 suggests that the alkyl chain has a significant contribution in
stabilising the forming biphasic system. Consistent with earlier
findings, the addition of polymeric surfactants was beneficial, but
its effect was more pronounced in the case of alkyl chain-free cat-
alyst 3. Interestingly, a two-fold increase in the ee was observed in
this case in PPG-containing reactions (8% (S) and 16% (S) without
and with PPG, respectively) while for catalyst 2 the ee remained
unchanged in the presence of PPG. Although it seems that alkyl
chains are important elements of the working catalyst, without
the aromatic ring, the alkyl chain itself is not sufficient for efficient
reaction. Catalysts 4 and 5 having n-pentyl and n-tridecyl chains,
respectively, but lacking the aromatic moiety both delivered
weaker results compared to 1. It is also clear from the data that
the longer alkyl chains have a stronger negative impact on the
reaction. While the n-pentyl catalyst 4 promoted the reaction with
56% conversion, with the n-tridecyl catalyst 5 no reaction occurred.
Interestingly, in both cases no ee was obtained. This finding is com-
parable with results obtained by Hayashi et al. using proline-based
surfactants similar to 4 and 5.44 Although their catalytic system
was different in not containing salt additives and the amount of
water was 18 equiv (compared to 222 equiv in our case) relative
to the aldehyde. Nonetheless, they observed the tendency of
decreasing yields with increasing side-chain length, although the
ees remained high (95–99%) in all cases. The dependence of the
catalytic activity on the alkyl chain length in biphasic aldol reac-
tions has been observed by Li et al., showing that longer chains
formed unstable emulsions leading to less efficient reactions.45
Interestingly, expanding the aromatic moiety from a phenyl
ring to a naphthyl ring system influenced the activity depending
on the topology of the catalyst. Catalyst 6 having 2-naphthoyl ring
system was virtually inactive in the reaction, although with PPG-
425 additive the results could be moderately improved. On the
other hand, compound 7 containing 1-naphthoyl moiety found to
be similar in activity to catalyst 1.
Table 3
The effect of the counter ion in acetate salts on the reaction between acetone and
2-nitrobenzaldehyde catalysed by 1 in the presence of watera
Entry Salt additive [mmol] Conversion [%]b Selectivity [%]b,c ee [%]b
1
LiOAc (7.6)
LiOAc (7.6)
KOAc (5.1)
KOAc (5.1)
CsOAc (2.6)
CsOAc (5.2)
CsOAc (2.6)
nBu4NOAc (1.7)
nBu4NOAc (1.7)
78
77
78
84
81
82
77
11
61
84
93
83
95
82
83
95
86
84
7 (S)
10 (S)
18 (S)
20 (S)
18 (S)
18 (S)
21 (S)
22 (S)
26 (S)
2d
3
4d
5
6
7d
8
9d
a
Reaction conditions: 0.5 mmol aldehyde, 2 mmol acetone, 30 mol % catalyst,
2 mL water, rt, 6 h.
b
Determined by chiral GC-FID analyses. (See also Section S1, ESI.)
Selectivity of the aldol product.
0.95 mmol PPG-425 was used as additive.
c
d
As the role of the catalyst is also to stabilize the forming bipha-
sic micellar system, decreasing its amount from 30 mol % to
15 mol % relative to the aldehyde resulted in lower conversion
and lower ee of the (S)-product (Table 4). Doubling the catalyst
amount (60 mol %) had no significant effect on the reaction
(Table 4, entry 4).
Table 4
The effect of the amount of catalyst
1 on the reaction between acetone and
2-nitrobenzaldehyde in the presence of watera
Entry Amount of 1 [mol %] Conversion [%]b Selectivity [%]b,c ee [%]b
1d
2
15
30
30
60
54
91
92
85
73
83
96
80
16 (S)
20 (S)
22 (S)
20 (S)
3d
4
a
Reaction conditions: 0.5 mmol aldehyde, 2 mmol acetone, 6.1 mmol NaOAc,
2 mL water, rt, 6 h.
We also wanted to explore the importance of the conforma-
tional freedom in the catalyst structure. Two approaches were fol-
lowed: (i) introducing additional freedom to efficient catalysts 1
b
Determined by chiral GC-FID analyses. (See also Section S1, ESI.)
Selectivity of the aldol product.
0.48 mmol PEG-1000 was used as additive.
c
d

A. A. Gurka et al. / Tetrahedron: Asymmetry 27 (2016) 936–942
939
O
C(%): 76 (69)
S(%): 91 (97)
O
O
OMe
Ee(%): 2 R (14)
N
H
11
O
O
O
O
O
O
N
H
O
N
H
OH
OH
C(%): 37 (88)
O
O
S(%): 94 (98)
7
6
Ee(%): 2 R (20)
N
H
OH
C(%): 9 (54)
S(%): 89 (96)
Ee(%): 0 (20)
C(%): 82 (92)
S(%): 88 (97)
Ee(%): 16 (18)
10
O
4
O
N
O
H2
O
O
OH
Cl
O
O
O
O
9a
O
O
N
N
H
N
H
H
OH
C(%): 4 (15)
S(%): 95 (99)
Ee(%): 4 (6)
OH
OH
1
2
3
C(%): 91 (94)
S(%): 83 (95)
C(%): 71 (82)
S(%): 84 (96)
Ee(%): 16 (16)
C(%): 26 (75)
S(%): 63 (98)
Ee(%): 8 (16)
Ee(%): 20 (20)
O
O
N
H
OH
9b
O
O
3
C(%): (66)
S(%): (96)
O
O
O
C(%): 56 (91)
S(%): 99 (96)
Ee(%): 3 R (16)
O
Ee(%): (14)
N
N
H
H
OH
OH
8
4
C(%): 79 (86)
S(%): 84 (96)
Ee(%): 16 (20)
O
11
O
C(%): 3 (67)
S(%): 99 (96)
Ee(%): 2 (10)
O
N
H
OH
5
Figure 3. The effect of the structure of L-hydroxyproline derived catalysts on the reaction of acetone and 2-nitrobenzaldehyde in aqueous NaOAc solution. Reaction
conditions: 0.5 mmol 2-nitrobenzaldehyde, 2 mmol acetone, 6.1 mmol NaOAc, 2 mL water, rt, 6 h. C—conversion, S—selectivity of the aldol product, Ee—enantioselectivity.
The ee values correspond to the (S)-product in all cases, otherwise noticed. Values in parentheses correspond to the reaction performed in the presence of PPG-425
(0.95 mmol) additive.
and 7 by introducing a methylene group between the aromatic
rings and the carboxylate oxo-group and (ii) introducing confor-
mational freedom to less efficient catalyst 3 by removing the car-
boxylate oxo-group from the structure. Thus, we tested
carboxylates 8 and 10 and ethers 9a and 9b. The HCl-salt 9a failed
to catalyse the reaction while 9b (tested only with PPG-425 addi-
tive) delivered similar results as parent compound 3. It has to be
noted, that the use of acidic additives in the 1/NaOAc system was
also disadvantageous to the reaction. While adding pTSA
(0.5 mmol), a decreased conversion of 42% (vs 91% without acid)
was obtained with 12% (S) ee (vs 20% (S) without acid), the same
amount of benzoic acid resulted in only 30% conversion with no
enantioselectivity in this case (for further details, see Table S3, ESI).
This is in line with earlier findings on the lack of beneficial effect
of Brønsted acidic (and basic) additives on ketone-aldehyde aldol
reactions.46
The introduction of conformational freedom affected catalysts 8
and 10 differently. While the tBu-chain containing molecule 8 suf-
fered only a moderate loss of activity in comparison to 1 (C = 79 vs
91%, S = 84 vs 83%, ee = 16 (S) vs 20% (S)), this decrease of activity
was more pronounced with compound 10 in relation to 7 (C = 37
vs 82%, S = 94 vs 88%, ee = 2 (R) vs 16% (S)). This suggests that

940
A. A. Gurka et al. / Tetrahedron: Asymmetry 27 (2016) 936–942
although the added conformational freedom to the catalyst is not
beneficial for the reaction, its negative impact could be overcom-
pensated by the alkyl chain probably due to its contribution to
emulsion stability. Furthermore, as observed previously, the addi-
tion of PPG-425 had a stronger positive effect on the weaker cata-
lysts 8 and 10, resulting in improved conversion and selectivity
values comparable to that of parent compounds 1 and 7. This is
especially true for the ee obtained with catalyst 10 (ee = 2% (R) vs
16% (S) without and with PPG-425, respectively).
Importantly, the additive dependent dual control of enantiose-
lectivity remained with all the catalysts as is clear from the results
obtained with NH4Cl as additive (Table 6). Furthermore, the ten-
dencies in activity can be paralleled with the results obtained
under the basic (NaOAc) conditions. Under both conditions catalyst
1, 2, 7 and 8 provided the best conversions. This suggests that these
catalysts are better in stabilizing the biphasic system that allows
the reactions to occur.
solubilize the weakly performing catalysts, thus improving their
availability for the reactants.
We also studied the reaction with respect to the aldehyde struc-
ture (Table 8). We found that the influence of the aldehyde struc-
ture is reflected mostly in the selectivity of the aldol product and to
Table 8
Influence of the aldehyde structure in the aldol reaction of different aldehydes with
acetone catalysed by 1 in the presence of aqueous NaOAc solutiona
1
Cat. (30 mol%)
O
OH
O
NaOAc (6.1 mmol)
O
+
R
H
R
H2O, rt
12 a-k
13 a-k
Aldehyde
Nr.
Aldehyde
Conversion
[%]b
Selectivity
[%]b,c
ee
[%]b
O
Table 6
Aldol reaction between 2-nitrobenzaldehyde and acetone in aqueous NH4Cl solutiona
H
H
12a
12b
91
89
83
64
20 (S)
26 (S)
Entry
Catalyst
Conversion [%]b
Selectivity [%]b,c
ee [%]b
NO2
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
45
47
14
19
16
17
46
55
50
81
71
99
89
91
88
92
68
79
56 (R)
68 (R)
76 (R)
82 (R)
72 (R)
60 (R)
74 (R)
62 (R)
73 (R)
O
NO2
O
10
H
12c
12d
12e
12f
85
80
81
86
14
68
64
24
31
73
18
15
20 (S)
32 (S)
32 (S)
19 (S)
8 (S)
a
Reaction conditions: 0.5 mmol aldehyde, 2 mmol acetone, 30 mol % catalyst,
1.9 mmol NH4Cl, 1.7 mL water, 50 °C, 6 h.
O2N
b
O
Determined by chiral GC-FID analyses. (See also Section S1, ESI.)
Selectivity of the aldol product.
c
H
It is clear from the results that the catalyst structure has a
‘physical’ role of stabilising the forming biphasic system and a
‘chemical’ role of catalysing the reaction (for further details see
Fig. S1, ESI). We studied the catalyst performance in acetone as
the solvent in an attempt to disconnect these two effects (Table 7).
In fact, some of our findings regarding the effect of structure on
catalytic activity in aqueous conditions are also reflected in the
reactions performed in acetone. A catching similarity is the low
activity of 2-naphthoyl catalyst 6 and 10 containing 1-napthy-
lacetyl moiety. This decreased activity is most likely originating
from their lower solubility in acetone. Both in the presence of
water and in acetone as solvent the proline moiety have to be
available for the reactants in order to promote the reaction. In this
respect, the PPG-425 additive has an important role in aiding to
Cl
O
H
Br
O
H
NC
tBu
O
H
12g
12h
O
H
22 (S)
OMe
O
Table 7
Aldol reaction between 2-nitrobenzaldehyde and acetone catalysed by hydroxypro-
line derivatives in acetone as the solventa
H
12i
68
18
28 (S)
Entry
Catalyst
Conversion [%]b
Selectivity [%]b,c
ee [%]b
OMe
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
92
81
88
96
82
43
91
86
54
84
98
97
93
94
97
99
98
93
98
93
88 (R)
77 (R)
86 (R)
86 (R)
88 (R)
86 (R)
89 (R)
86 (R)
88 (R)
60 (R)
OMe
O
H
12j
92
17
68
8
18 (S)
28 (S)
N
O
12k
H
10
11
a
a
Reaction conditions: 0.5 mmol aldehyde, 30 mol % catalyst, 2 mL acetone, rt,
Reaction conditions: 0.5 mmol aldehyde, 2 mmol acetone, 30 mol % catalyst,
6 h.
6.1 mmol NaOAc, 2 mL water, rt, 6 h.
b
b
Determined by chiral GC-FID analyses. (See also Section S1, ESI.)
Selectivity of the aldol product.
Determined by chiral GC-FID analyses. (See also Section S1, ESI.)
c
c
Selectivity of the aldol product.

A. A. Gurka et al. / Tetrahedron: Asymmetry 27 (2016) 936–942
941
a lesser extent in the conversion and ee values. In the case of 4-tert-
butylbenzaldehyde and 2-naphthaldehyde (Table 8, aldehydes 12g
and 12k) the low conversions were related to the steric hindrance
of the bulky tert-butylphenyl and naphthyl moieties, and their
lower solubility in the acetone phase could be a limiting factor as
well (see also Table S2, ESI). It is noteworthy that the selectivity
of the aldol reaction is much higher for aromatic aldehydes con-
taining electron withdrawing groups that can be explained by
the lower rate of the elimination step in their case, which would
lead to the corresponding condensation product.
From a mechanistic point, when using proline derivatives such
as compound 1 as catalysts in aldol reactions in the presence of
water, the formation of ‘water/oil’ interface is crucial for the reac-
tions to take place.41,44,45,47–52 Hydrogen-bonding interactions of
the transition state with interfacial O–H groups that protrude into
the organic phase likely facilitate the reaction.53
the hydroxyproline derived catalyst structure showed that both an
aromatic ring and an alkyl chain are necessary for a working cata-
lyst. Furthermore, the rigidity of the catalyst structure was also
found to be an important factor. Although our studies provided
an overview on the catalyst structures and conditions under which
the reactions can be performed, these parameters were found to be
less influential on the enantioselectivity values, as generally low or
moderate ees were obtained. This is especially true for the (S)-aldol
product, forming under basic conditions, that is having the oppo-
site stereochemistry to what is accessible under ʟ-proline catalysis
in organic media. Although achieving dual stereocontrol in aque-
ous aldol reactions, especially with water soluble reactants,
remains a challenge, we believe that our contribution enriches
the toolbox of enantiodivergent synthetic methodology.
Acknowledgements
For the dual stereocontrol to occur, the reactions performed
under different conditions are suggested to have different transi-
tion states. Under acidic conditions (NH4Cl additive) the carboxylic
acid proton of proline directs the aldehyde through H-bonding so
that the Re-face of the aldehyde is attacked by the enamine, thus
providing stereocontrol for the reaction ((R) product forms in
excess, as in organic medium). On the other hand, under basic con-
ditions (NaOAc additive), when the catalyst is lacking the acidic
proton, the previously mentioned hydrogen-bond directed stereo-
chemical control does not operate.23 In this case we suggest (Fig. 4)
that the Si-face of the aldehyde may be more easily attacked by the
enamine, resulting in formation of opposite enantiomer [(S)-pro-
duct forms in excess]. This scenario could also be aided by interfa-
cial interactions between the organic phase and the aqueous phase
that directs the relative orientation of the reactants.54
Financial support from the National Research, Development and
Innovation Office, Hungary (OTKA Grants K 109278 and PD
115436) is gratefully acknowledged. Z. Szécsényi and R. Megyesi
(Institute of Pharmaceutical Chemistry, University of Szeged) are
acknowledged for technical support.
Supplementary data
Supplementary data (synthesis and characterisation of the cat-
alysts, enantiomer separation conditions, chromatograms, NMR
spectra) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetasy.2016.08.009.
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