Different bio/Lewis acid-catalyzed stereoselective aldol reactions in various mediums

Article abstract of DOI:10.1007/s00706-017-1967-z

In this work eight different crude biocatalysts together with six Lewis and three Br?nsted acids were used for asymmetric aldol reactions of aromatic, heteroaromatic, cyclic, and acyclic six ketones and eleven aldehydes. Optimum reaction conditions were d

Full text of DOI:10.1007/s00706-017-1967-z

Monatsh Chem
DOI 10.1007/s00706-017-1967-z
ORIGINAL PAPER
Different bio/Lewis acid-catalyzed stereoselective aldol reactions
in various mediums
1
Tu¨lay Yıldız1 Hasniye Yas¸a1 Belma Hasdemir1 Ays¸e S. Yusufoglu
•
•
•
˘
Received: 24 January 2017 / Accepted: 19 March 2017
Ó Springer-Verlag Wien 2017
Abstract In this work eight different crude biocatalysts
togetherwithsixLewis andthree Brønstedacidswereusedfor
asymmetric aldol reactions of aromatic, heteroaromatic,
cyclic, and acyclic six ketones and eleven aldehydes. Opti-
mum reaction conditions were determined by changing
temperature and enzyme, ketone, aldehyde, solvent, cofactors
types, amounts, and ratios. PPL (porcine pancreatic lipase) of
animal and AL-AN (amano lipase A from Aspergillus niger)
of fungal origins were the best ones and compared with each
other. CoCl2 was the best cofactor and catalyzed the enzy-
matic aldol reaction better than without cofactor. CoCl2 was
not used before for enzymatic aldol reactions. The method in
this study, using crude biocatalysts (PPL or AL-AN) and
CoCl2 in acetonitrile–water was found as an conventionally
useful biocatalytic way for asymmetric aldol reaction and has
given better ee values than in the literature.
Keywords Aldol condensation Á Biocatalytic promiscuity Á
Enzyme-catalyst Á Asymmetric reaction Á
Chiral keto alcohol
Introduction
Biocatalyst is considered in catalytic synthetic reactions as
a green tool because of its high selectivity, mild conditions,
low energy consumption, and side reactions [1–4]. Bio-
catalytic methods are demanded largely from the
pharmaceutical and chemical industries, due to their envi-
ronmental and green chemistry sensitivity and have been
worked widely in recent years [5–7].
Many types of enzyme are used in organic synthesis.
Particular lipase are successfully and increasingly applied
in the industrial fields such as agrochemicals, pharmaceu-
ticals, and natural compounds [8, 9], because of their good
stability, high catalytic effectivity, commercial availability,
and broad range of substrate specificity.
Graphical abstract
Even though lipases can catalyze the hydrolysis of ester
bonds, some hydrolytic lipases catalyze non-conventional
synthetic organic reactions, which have recently reported,
such as Michael additions [10–12], Mannich reactions
[13, 14], Markovnikov additions [15], Henry reactions
[16, 17], polymerization [18, 19], epoxidation [20–22], and
aldol reactions [23–27]. Many asymmetric aldol reactions
were achieved using organocatalysis such as proline or
proline derivatives [28–31]. Aldolases [32–35] which are
costly and unstable catalytic antibodies [36] and small
molecules [37] were also not successful in asymmetric
aldol reactions. Therefore, developing catalysts for asym-
metric aldol reaction has been a subject which continues to
attract the attention of researchers.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-1967-z) contains supplementary
material, which is available to authorized users.
˘
& Ays¸e S. Yusufoglu
ayseserg@istanbul.edu.tr
1
Department of Chemistry, University of Istanbul, 34320
Istanbul, Avcilar, Turkey
123

T. Yıldız et al.
However, there are a limited number of aldol reactions
catalyzed by lipases [38–40]. It was reported that wild
CAL-B and Ser105Ala mutant CAL-B have catalytic
activity on aldol reaction by Berglund and co-workers [38].
The previous studies showed that some lipases and pro-
teases can catalyze asymmetric aldol additions. One of
these is lipase from porcine pancreas (PPL) which was first
used in the enzyme-catalyzed asymmetric aldol addition
between acetone and different aromatic aldehydes in 2008
[39]. Then Yu and co-workers reported PPL-catalyzed
stereoselective cross-aldol reactions between aromatic
aldehydes and cyclic ketones in 2013 [41]. Another work
about direct asymmetric aldol reactions catalyzed by the
lipase from porcine pancreas was reported in 2014 [42].
In this study many asymmetric aldol reactions of various
aromatic, heteroaromatic, cyclic, and acyclic ketones and
aldehydes were investigated and catalyzed by different
crude biocatalysts and Lewis and Brønsted acids via
changing solvent, temperature, amounts, ratios, and
cofactors. AL-AN and PPL were the best ones. To obtain
better yields several Lewis and organic acids were studied
together with the crude biocatalysts mentioned for the first
time in this paper. CoCl2 was the best appropriated Lewis
acid with PPL and AL-AN. The medium CoCl2-MeCN-
H2O (10:1) was not used before for enzymatic aldol reac-
tions. The ketools 3a–3k and 4b–4g were not synthesized
before by the method in this paper (Tables 8 and 9). 4c and
4e are novel keto alcohols.
although AL-PF gave the best yield result, its ee was only
44%. Based on these results, PPL and AL-AN were
selected as biocatalyst for our enantioselective aldol
reaction.
Time is also an important parameter of the enzymatic
aldol reaction. We also checked the reaction time at regular
intervals, we observed that the yield was increased pleas-
ingly when the reaction period was raised, although the
selectivity remained nearly unchanged. The best yield and
selectivity was obtained for 4 days, in this study.
In the next step, to improve the ee results, some organic
solvents with a small amount of water were tried in the
same reaction conditions and same substrates (Table 2).
Although high selectivity we achieved as dr 90:10, ee 79%
for PPL, dr 89:11, ee 75% for AL-AN in MeCN (Table 2,
entry 3), the yield decreased to 65% and 63%. As seen
from the Table 2, the reaction between 1a and 2a with PPL
or AL-AN as catalyst kept on with substantially lower
results in non-polar solvents such as n-hexane and toluene.
Ethanol as a polar protic solvent was also not sufficient.
Polar aprotic solvents such as MeCN, DMSO, THF, and
DMF have given much better results than the others.
In consistence with previous reports [39, 40] and also
our experiments (Table 2, entry 9 and Table 3, entry 1) it
proved that water is an important factor in this enzymatic
reaction. Therefore, varying the ratio between solvent and
water revealed that 10:1 was the optimum ratio (Table 3).
However, the best yield was obtained for PPL when the
ratio of MeCN/H2O was 5:1 which gave the product in
68% yield (74% ee, 86:14 dr) (Table 3, entry 4). The best
selectivity was obtained with 10:1 ratio of MeCN/H2O as
the optimal ratio for the PPL or AL-AN-catalyzed aldol
reactions.
Results and discussion
Different biocatalysts demonstrated encouraging results
with good diastereoselectiviies and enantioselectivities
under solvent-free and no additive conditions in case of
using cyclohexanone (1a) and 4-nitrobenzaldehyde (2a)
over 6 days (Table 1). Six commercially available lipase
enzymes and two liver acetone powders which provide
low-cost crude lipase sources were used in aldolisation
reaction as crude biocatalysts. These are lipase from
Candida cylindracea (CCL), lipase from Candida rugosa
(CRL), porcine pancreatic lipase (PPL), amano lipase from
Burkholderica cepacia (Pseudomonas cepacia) (AL-PS),
amano lipase A from Aspergillus niger (AL-AN), amano
lipase from Pseudomonas fluorescens (AL-PF), liver ace-
tone powder-horse (LAP-H), and liver acetone powder-
guinea pig (LAP-GP). AL-PS, AL-PF, LAP-H and LAP-
GP were used as biocatalysts for the first time in this
enzymatic aldol reaction. It is shown in Table 1, entries 4
and 6, that PPL and AL-AN gave the best promiscuous
activity. Comparing with other lipases, PPL with nearly
85% yield and 75% ee was the best and AL-AN with 84%
yield and 74% ee was the second best one. Interestingly,
Moreover, we examined the effect of lipase concentra-
tion on the enzyme-catalyzed enzymatic aldol reaction
(Table 4). We found that the yield had a nice improvement
when the lipase concentration was increased from 10 to
200 mg/cm3. However, using much more enzyme could
not cause better selectivity. 50 and 100 mg/cm3 enzyme
concentration gave almost the same results. Based on the
selectivity, 50 mg/cm3 was chosen as the optimum enzyme
concentration (Table 4, entry 3). Although selectivity was
not raised too much, at least we achieved 80% for PPL and
76% AL-AN yield using 50 mg/cm3 enzyme amount.
Then, the efficiency of the molar ratio between aldehyde
and ketone (1a and 2a) was examined (Table 5) to increase
the yield and selectivity. Several molar ratios of 1a and 2a
from 1:1 to 20:1 were tested. The best enantioselectivity
was obtained as 20:1 for the ratio of 1a and 2a with 82% ee
for PPL (Table 5, entry 5). However, increasing the pro-
portion of ketone could not show a remarkable influence on
the enantioselectivity of the reaction, the yield was clearly
improved up to 87 and 78% for PPL and AL-AN,
123

Different bio/Lewis acid-catalyzed stereoselective aldol reactions in various mediums
Table 1 Screening of different crude biocatalysts for the asymmetric aldol reactions
Entry
Lipase
Yield/%
dr (anti:syn)a
ee/%a
1
2
3
4
5
6
7
8
9
No enzyme
CCL
0
45
36
85
81
84
92
20
0
–
–
67:33
68:32
85:15
63:37
76:24
70:30
52:48
–
50
42
75
20
74
44
20
–
CCR
PPL
AL-PS
AL-AN
AL-PF
LAP-H
LAP-GP
Conditions: 4-nitrobenzaldehyde (0.1 mmol), 2 cm3 cyclohexanone, and 20 mg lipase in 0.1 cm3 deionized water at room temperature for 4 days
a
ee and dr were determined by HPLC analysis using a chiral column
Table 2 Investigation of solvents for the enzymatic aldol reactions
Entry
Solvent
Yield/% AL-AN
Yield/% PPL
dr (anti:syn)a AL-AN
dr (anti:syn)a PPL
ee/%a AL-AN
ee/%a PPL
1
2
3
4
5
6
7
8
9
DMSO
81
42
63
12
18
15
75
84
45
82
46
65
10
22
12
76
85
75
75:25
65:35
89:11
54:46
75:25
61:39
80:20
76:24
72:28
77:23
66:34
90:10
57:43
84:16
62:38
81:19
85:15
80:10
56
25
75
15
65
18
66
74
42
57
28
79
20
72
20
68
75
57
EtOH
MeCN
Hexane
THF
Toluene
DMF
Cyclohexanone
Cyclohexanoneb
Conditions: 4-nitrobenzaldehyde (0.1 mmol), cyclohexanone (1 mmol), and enzyme [PPL: 20 mg (0.48 kU), AL-AN: 20 mg (2.4 kU)] in
organic solvent and deionized water (10:1, 1 cm3) at room temperature for 4 days
a
ee and dr were determined by HPLC analysis using a chiral column
b
No water
respectively (Table 5, entry 5). Therefore, for further
studies, the molar ratio of cyclohexanone to 4-nitroben-
zaldehyde was determined 20:1 as the optimal ratio.
A large factor of their convenient suitability in living
systems is that an important fraction of enzymes needs
metals for their catalytic activity. Many metal-bonded
enzymes are found in nature which act in fundamental
biological processes, including photosynthesis, respiration,
and nitrogen fixation [43].
The system of Lewis-acid and organocatalytic activation
is inspired from enzymatic mechanism in the nature
[44, 45]. Herein we tried for the first time the Lewis acid or
Brønsted acid/bio-catalyzed aldol reactions. For this, we
tested a series of metal salts or some natural acids as
cofactor (Table 6).
We had very interesting results in this step using Lewis-
acid as cofactor in enzymatic aldol reactions. Based on
Table 6, the best enantioselectivity was obtained by CoCl2
123

T. Yıldız et al.
Table 3 Effect of MeCN/water ratio for the enzymatic aldol reactions
Entry
MeCN/H2O
Yield/% AL-AN
Yield/% PPL
dr (anti:syn)a AL-AN
dr (anti:syn)a PPL
ee/%a AL-AN
ee/%a PPL
1
2
3
4
5
7
No water
1:1
15
60
61
65
63
62
27
62
65
68
65
64
75:25
76:24
83:17
85:15
89:11
88:12
83:17
76:24
85:15
86:14
90:10
90:10
60
51
68
67
75
71
62
50
70
74
79
77
2:1
5:1
10:1
20:1
Conditions: 4-nitrobenzaldehyde (0.1 mmol), cyclohexanone (1 mmol), and enzyme [PPL: 20 mg (0.48 kU), AL-AN: 20 mg (2.4 kU)] in MeCN
and deionized water (1 cm3) at room temperature for 4 days
a
ee and dr were determined by HPLC analysis using a chiral column
Table 4 Investigation of enzyme concentration on the lipase-catalyzed enzymatic aldol reactions
Entry Enzyme conc./mg cm-3 Yield/% AL-AN Yield/% PPL dr (anti:syn)a AL-AN dr (anti:syn)a PPL ee/%a AL-AN ee/%a PPL
1
2
3
4
5
10
20
34
63
75
76
72
45
65
80
81
75
85:15
89:11
89:11
88:12
86:14
87:13
90:10
90:10
89:11
85:15
64
75
76
74
65
75
79
80
80
78
50
100
200
Condition: 4-nitrobenzaldehyde (0.1 mmol), cyclohexanone (1 mmol), and enzyme in MeCN and deionized water (10:1, 1 cm3) at room
temperature for 4 days
a
ee and dr were determined by HPLC analysis using a chiral column
as cofactor with 88% ee for PPL and 79% ee for AL-AN at
room temperature. Their yields also were lower as 75 and
60% (Table 6, entry 5). To increase the yield we studied
the reaction at 37 °C (Table 6, entry 6). Surprisingly the
yields increased to 95% for PPL and 82% for AL-AN, the
enantioselectivity of PPL stayed at the same value with
88% and the enantioselectivity of AL-AN was increased
slightly to 80% at 37 °C.
Further investigation about the amount of cobalt salt in
the enzymatic aldol reaction was carried out with PPL
(Table 7). Various amounts were studied at this point and it
was seen that the increasing amount of cobalt decreased the
yield and selectivity (Table 7). Increasing in the amount of
cobalt showed a deactivating effect on the enzyme.
Therefore, the best amount was determined with 20% mol.
Also when the enzyme (PPL) was not used in the reaction
with CoCl2, it was found that the yield was almost none
and there was no selectivity (Table 7, entry 4).
Various aromatic aldehydes were tested in the reac-
tion (Table 8). Also a wide range of ketones having
different structures were explored in the lipase/CoCl2-
catalyzed aldol reaction. As seen from Table 8, the steric
hindrance had no significant effect on aldehydes of dif-
ferent structures. Good selectivities were achieved when
using benzaldehyde having either electron-withdrawing
or electron-donating substituents. PPL or AL-AN/CoCl2
combination gave almost equal enantioselectivity for
aldol reaction of aromatic aldehydes and cyclohexanone.
However, yields were obtained with good values of
67–95% for PPL, 50–92% for AL-AN. While the best
enantioselectivity with PPL was achieved by 2-naph-
thaldehyde and 4-methoxybenzaldehyde with 92% ee
123

Different bio/Lewis acid-catalyzed stereoselective aldol reactions in various mediums
Table 5 Influence of ketone/aldehyde molar ratio for the enzymatic aldol reactions
Entry
1a/2a
Yield/% AL-AN
Yield/% PPL
dr (anti:syn)a AL-AN
dr (anti:syn)a PPL
ee/%a AL-AN
ee/%a PPL
1
2
3
4
5
1:1
51
58
61
75
78
60
62
65
80
87
74:26
75:25
82:18
89:11
88:12
86:14
81:19
86:14
90:10
89:11
71
72
73
76
76
76
76
74
80
82
2:1
5:1
10:1
20:1
Conditions: 4-nitrobenzaldehyde (0.1 mmol), cyclohexanone, and enzyme [PPL: 50 mg (1.2 kU), AL-AN: 50 mg (6 kU)] in MeCN and
deionized water (10:1, 1 cm3) at room temperature for 4 days
a
ee and dr were determined by HPLC analysis using a chiral column
Table 6 Screening of cofactor for the enzymatic aldol reactions
Entry
Cofactor (20%)
Yield/% AL-AN
Yield/% PPL
dr (anti:syn)a AL-AN
dr (anti:syn)a PPL
ee/%a AL-AN
ee/%a PPL
1
2
No
78
45
51
35
60
82
25
53
52
94
87
53
56
42
75
95
35
60
56
95
88:12
86:14
90:10
85:15
89:11
88:12
61:39
83:17
80:20
53:47
89:11
90:10
92:8
76
76
78
78
79
80
65
73
74
50
82
82
86
86
88
88
70
84
85
45
Cu(OTf)2
FeCl3
3
4
MnCl2
88:12
93:7
5
CoCl2
CoClb2
6
90:10
66:34
87:13
85:15
58:42
7
ZnCl2
8
Mandalic acid
Lactic acid
Benzoic acid
9
10
Conditions: 4-nitrobenzaldehyde (0.1 mmol), cyclohexanone (2 mmol), cofactor (20%), and enzyme [PPL: 50 mg (1.2 kU), AL-AN: 50 mg (6
kU)] in MeCN and deionized water (10:1, 1 cm3) at room temperature for 4 days
a
ee and dr were determined by HPLC analysis using a chiral column
b
At 37 °C
(Table 8, entry 6 and 9), the best enantioselectivity with
AL-AN was obtained by 2-furylaldehyde with 85% ee
(Table 8, entry 7). We used also different ketones as
aldol donors with 4-nitrobenzaldehyde, and we observed
interesting results (Table 9). At this stage, we tried some
ketones (1c, 1d and 1f) for the first time on the enzy-
matic direct aldol reaction.
(Table 6, entry 1) than with CoCl2 (Table 6, entry 6).
Consequently, the best biocatalyst PPL with CoCl2 in
acetonitrile increased the enantioselectivity from 82 to
88%.
According to the literature [38, 41, 46] lipase sorts are
described as having three amino acids residues Asp, His,
Ser in their active sites. Due to these literature studies,
histidine may be the most active edge of PPL and AL-AN
in aldolisation. In this work is suggested that CoCl2 has
activated histidine residue more than the other active
centers, so that better ee values were achieved in this
aldolisation study.
In the absence of crude biocatalyst, the mentioned aldol
reactions did not occur in this study (Table 1, entry 1). If
CoCl2 was used alone, it almost did not give any aldoli-
sation reaction (Table 7, entry 4). The best biocatalyst PPL
without CoCl2 gave the aldol reaction with lower ee value
123

T. Yıldız et al.
ee/%a
Table 7 Effect of CoCl2
amount for the enzymatic aldol
reactions with PPL
Entry
CoCl2/%mol
Yield/%
dr (anti:syn)a
1
2
3
4
5
6
7
8
No
10
97
94
95
2
88:12
89:11
90:10
60:40
87:13
86:14
82:18
80:20
82
87
88
0
20
20b
50
90
85
55
43
86
84
83
75
75
100
150
Conditions: 4-nitrobenzaldehyde (0.1 mmol), cyclohexanone (2 mmol), CoCl2, and PPL [50 mg (1.2 kU)]
in MeCN and deionized water (10:1, 1 cm3) at 37 °C for 4 days
a
ee and dr were determined by HPLC analysis using a chiral column
b
No enzyme
Table 8 Scope of aromatic aldehydes for the enzymatic aldol reactions of cyclohexanone by lipase/CoCl2
Entry Aldehyde
R
Yield/%a AL-AN Yield/%a PPL dr (anti:syn)b AL-AN dr (anti:syn)b PPL ee/%b AL-AN ee/%b PPL
1
2a
2b
2c
2d
2e
2f
4-NO2C6H4
C6H5
82
76
62
71
95
92
68
76
90
67
88
92
95
81
74
88:12
82:18
86:14
83:17
90:10
90:10
75:25
85:15
89:11
88:12
88:12
90:10
83:17
88:12
85:15
96:4
80
79
81
80
66
84
85
81
86
82
81
88
86
88
88
70
92
90
88
92
86
88
2
3
2-CH3C6H4
3-CH3C6H4
4
5
2-CH3OC6H4 85
4-CH3OC6H4 50
6
89:11
70:30
88:12
92:8
7
2g
2h
2i
2-Furyl
76
85
92
75
68
8
2-Thienyl
2-Naphthyl
2-FC6H4
2-BrC6H4
9
10
11
2j
92:8
2k
87:13
Conditions: aldehyde (0.1 mmol), cyclohexanone (2 mmol), CoCl2 (20%), and enzyme [PPL: 50 mg (1.2 kU), AL-AN: 50 mg (6 kU)] in MeCN
and deionized water (10:1, 1 cm3) at 37 °C for 4–6 days
a
Isolated yield of products
b
ee and dr were determined by HPLC analysis using a chiral column
Therefore, we used both lipases in all reactions and com-
pared the animal-derived (PPL) with fungal-derived (AL-
AN). As seen from the results, PPL gave slightly better
yields and enantioselectivities than AL-AN.
Conclusion
In summary, the study of developing new crude bio-Lewis
acid-catalyzed aldol reaction between aromatic aldehydes
and cyclic-acyclic ketones led us to find some innovations.
In this context, we investigated so many effects such as
lipase, solvents, cofactor types, water contents, tempera-
ture, molar ratio of substrates and enzyme concentrations
on the enzyme-catalyzed aldol reaction to find the best
enantioselectivity. After a broad screening of lipases, PPL
and AL-AN gave the highest stereoselectivities and yields.
The optimized PPL or AL-AN/CoCl2-catalyzed reaction
conditions gave anti-products with better enantioselectivi-
ties between 80 and 100% ee when compared with other
enzyme-catalyzed procedures. Finally a green, cheap, and
novel protocol was developed as an example of enzymatic
promiscuity using a combination of PPL or AL-AN/CoCl2
as biocatalyst.
123

Different bio/Lewis acid-catalyzed stereoselective aldol reactions in various mediums
Table 9 Screening of various structured ketones for the enzymatic aldol reactions with 4-nitrobenzaldehyde by lipase/CoCl2
Entry
1
Ketone
Product
Yield/%a
AL-AN
Yield/%a
PPL
dr (anti:syn)b
AL-AN
dr (anti:syn)b
PPL
ee/%b
AL-AN
ee/%b
PPL
O
OH
O
80
85
–
–
62
66
4b
4c
1b
O
NO2
O
OH
C5H11
2
3
4
5
6
60
42
30
66
90
64
45
25
69
95
–
–
48
51
C5H11
1c
NO2
O
OH
O
Ph
–
–
37
38
4d
4e
1d
NO2
O
NO2
O
55:45
56:44
90:10
53:47
62:38
93:7
78/76c
37
99/96c
42
Ph
1d
OH
O
O
OH
4f
4g
NO2
1f
O
HO
O
87
98
NO2
1g
Conditions: 4-nitrobenzaldehyde (0.1 mmol), ketone (2 mmol), CoCl2 (20%), and enzyme [PPL: 50 mg (1.2 kU), AL-AN: 50 mg (6 kU)] in
MeCN and deionized water (10:1, 1 cm3) at 37 °C for 4–6 days
a
Isolated yield of products
b
ee and dr were determined by HPLC analysis using a chiral column
c
The ee values for anti/syn
1 cm3) were added to a flask then the mixture was stirred at
Experimental
37 °C for 4–6 days. The reaction extracted with ethyl acetate
three times. The combined extractsweredried overanhydrous
Na2SO4, and the solvents were then removed under reduced
pressure. Reactions were monitored by thin-layer chro-
matography and visualized using UV light. After finishing of
the reaction, the product was first analyzed by HPLC. For
determination of the isolated yield, flash chromatography was
performed on silica gel (Merck; 230–400 mesh) with hexane–
ethyl acetate (v/v 9:1) as the mobile phase. Racemic com-
pounds of all aldol products were synthesized by known
methods as references for HPLC.
The majority of the chemicals and all enzymes used in this
work were commercially available from Merck or Sigma-
Aldrich. All reagents were obtained from commercial sup-
pliers and were used without further purification unless
otherwise noted. Lipase from porcine pancreas, type II (42 U/
mgprotein;proteinbybiuret:56%;oneunitwillhydrolyze1.0
microequivalent of fatty acid from triacetin within 1 h at pH
7.4 and 37 °C), amano lipase A from A. niger (120,000 U/g;
one unit is defined as the amount of enzyme to liberate
0.1 lmol fatty acid from olive oil per min at pH 6.0 and
37 °C). The reactions were monitored by TLC using silica gel
plates and the products were purified by flash column chro-
matography on silica gel (Merck; 230–400 mesh).
Characterization data for compounds already described in
the literature can be found in the Supplementary Material.
The NMR spectra were recorded at 500 MHz for 1H and
125 MHz for 13C using Me4Si as the internal standard in
CDCl3. HPLC was performed on a Shimadzu/DGU-20A5
HPLC apparatus fitted with a 25 cm Chiralcel OD and
Chiralpac AD-H chiral columns. Optical rotations were
measured with Optical Activity AA-55 digital polarimeter
at room temperature.
1-Hydroxy-1-(4-nitrophenyl)-octan-3-one
(4c, C14H19NO4)
25
D
Yield 64%; enantiomeric excess 51%; ½aŠ = ?18.5
ꢀ
(c = 0.9, CHCl3); IR (neat): m = 3469, 3069, 2938,
2892, 1679, 1600, 1492, 1292, 1253, 984, 761 cm-1; H
1
NMR (500 MHz, CDCl3): d = 8.14 (d, J = 9 Hz, 2H),
7.46 (d, J = 8.5 Hz, 2H), 5.19 (dd, J1 = 4 Hz,
J2 = 8.5 Hz, 1H), 3.56 (brs, 1H), 2.73–2.76 (m, 2H),
2.37 (t, J = 7 Hz, 2H), 1.49–1.55 (m, 2H), 1.15–1.25 (m,
4H), 0.82 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3): d = 211.3, 150.3, 147.5, 126.7, 126.5, 124.0,
123.8, 69.2, 50.47, 43.8, 31.4, 23.4, 22.5, 14.0 ppm.
General procedure for the aldol reaction
Aromatic aldehyde (0.1 mmol), ketone (2 mmol), CoCl2
(20%), and PPL (50 mg) in MeCN and deionized water (10:1,
123

T. Yıldız et al.
15. Wu WB, Wang N, Xu JM, Wu Q, Lin XF (2005) Chem Commun
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145:240
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63:62
Enantiomeric excess of anti-diastereomer was deter-
mined by HPLC with a CHIRALPAK AD-H column (95:5
hexane:2-propanol), 25 °C, 263 nm, 1.0 cm3/min; major
enantiomer
tR = 37.5 min,
minor
enantiomer
tR = 35.4 min.
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Baldessari A (2010) Polymer 51:2998
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4-Hydroxy-4-(4-nitrophenyl)-3-phenylbutan-2-one
(4e, C16H15NO4)
Yield 25%; dr (anti:syn) 54:47; enantiomeric excess 99%
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for anti, 96% for syn; IR (neat): = 3472, 3065, 2946, 2889,
1
1685, 1606, 1499, 1292, 1242, 988, 763 cm-1; H NMR
(500 MHz, CDCl3): d = 8.00 (d, J = 9 Hz, 2H),
7.19–7.23 (m, 5H), 6.96–6.97 (m, 2H), 5.44 (dd,
J1 = 2 Hz, J2 = 4.5 Hz, 1H), 3.82 (d, J = 4.5 Hz, 1H),
3.36 (d, J = 2 Hz, 1H), 1.99 (s, 3H), 1.18 (brs, 1H) ppm;
13C NMR (125 MHz, CDCl3): d = 209.3, 148.7, 147.4,
132.7, 130.0, 129.9, 129.1, 128.9, 127.5, 123.5, 124.4,
72.9, 72.9, 65.9, 65.8, 30.1 ppm.
Enantiomeric excess of diastereomers was determined by
HPLC with a CHIRALPAK AD-H column (90:10 hexane:2-
propanol), 25 °C, 210 nm, 1.0 cm3/min; for anti-diastere-
omer major enantiomer tR = 37.9 min, minor enantiomer
tR = 23.2 min; for syn diastereomer major enantiomer
tR = 24.6 min, minor enantiomer tR = 30.1 min.
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32. Eyrisch O, Fessner WD (1995) Angew Chem Int Ed 34:1639
33. Kimura T, Vassilev VP, Shen GJ, Wong CH (1997) J Am Chem
Soc 119:11734
Acknowledgements This study was supported by The Scientific and
˙
¨
Technological Research Council of Turkey (TUBITAK) with Project
Number 214Z234.
34. Espelt L, Parella T, Bujons J, Solans C, Joglar J, Delgado A,
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