Chemoenzymatic synthesis of optically active 2-(2′- or 4′-substituted-1H-imidazol-1-yl)cycloalkanols: Chiral additives for (l)-proline

Article abstract of DOI:10.1039/c3cy00107e

Enantiopure substituted imidazoles obtained by enzymatic kinetic resolution can be promising candidates as co-catalysts for aldol reactions catalysed by (l)-proline. These additives seem to form supramolecular complexes with the catalyst through the forma

Full text of DOI:10.1039/c3cy00107e

Catalysis
Science & Technology
View Article Online
View Journal
PAPER
Chemoenzymatic synthesis of optically active
2-(20- or 40-substituted-1H-imidazol-1-yl)cycloalkanols:
chiral additives for (L)-proline†
Cite this: DOI: 10.1039/c3cy00107e
a
b
b
b
´
´
´
´
Raul Porcar, Nicolas Rıos-Lombardıa, Eduardo Busto, Vicente Gotor-Fernandez,
Vicente Gotor,*b Eduardo Garcia-Verdugo,a M. Isabel Burguetea and Santiago V. Luis*a
Enantiopure substituted imidazoles obtained by enzymatic kinetic resolution can be promising
candidates as co-catalysts for aldol reactions catalysed by (L)-proline. These additives seem to form
supramolecular complexes with the catalyst through the formation of H-bonds, leading to significant
improvement in both the reaction rates and selectivity of the reaction. Herein, we present our results
on the use of these substituted trans-2-imidazoyl-cycloalkanols as additives for the (L)-proline catalyzed
direct aldol reaction between ketones and aromatic aldehydes.
Received 14th February 2013,
Accepted 29th March 2013
DOI: 10.1039/c3cy00107e
www.rsc.org/catalysis
strategies have been assayed to achieve this goal, but, in general,
all of them required the re-design, re-synthesis, and re-selection
Introduction
Organocatalysis is gaining importance as an environmentally
friendly alternative to well established asymmetric transformations
based on metal-containing catalysts.1 Thus, it is becoming a
common tool in synthetic organic chemistry. From the toolbox
of small organocatalysts, proline is by far one of the most popular
ones, as it is cheap, readily available in both enantiomeric forms
and can be used for a wide range of synthetic transformations.2
Among them the direct catalytic aldol reaction is a well-studied
and broadly applicable C–C bond-forming reaction, which
provides enantiomerically enriched b-hydroxy carbonyl compounds.3
However, (L)-proline itself presents some major drawbacks,
presenting a poor solubility and reactivity in non-polar organic
solvents, and can lead to parasitic side reactions that signifi-
cantly reduce the selective conversion of the aldehyde into the
corresponding aldol, requiring high catalyst loadings in order
to achieve acceptable yields.4 Therefore, much effort has been
devoted to the development of new organocatalysts based on
structurally modified (L)-prolines.5 The design and synthesis of
these new organocatalysts does not only allow modifying their
physical properties but also may lead, in some cases, to more
efficient and enantioselective processes. Different synthetic
of efficient organocatalysts, limiting, to some extent, the scope of
this approach. A simpler alternative is the use of different types
of additives, whose addition to the reaction containing the
(L)-proline will help to modify its outcome in terms of yield
and selectivity. This allows a fast design and evaluation of a new
series of catalytic systems by simply tuning the nature of the
selected additive. Thus, different additives6 such as alcohols,7
ureas and thioureas,8 guanidinium salts,9 amine bases10 or the
simple addition of water11 have been reported to accelerate the
reaction rate and to increase its diastereo- and enantioselectivity.
We have recently reported a general chemoenzymatic
methodology to produce optically active trans-2-imidazoyl-
cycloalkanols.12 These functionalised chiral imidazole derivatives
may interact with the organocatalyst through H-bonding and/or
by acid–base mechanisms leading to the formation of the corres-
ponding chiral salts. This may provide mechanisms allowing us to
fine-tune the catalytic properties of (L)-proline. Herein, we present
our results on the use of these substituted trans-2-imidazoyl-
cycloalkanols as additives for the (L)-proline catalyzed direct aldol
reaction between ketones and aromatic aldehydes.
Results and discussion
a
´
´
´
Departamento de Quımica Inorganica y Organica, Universitat Jaume I Av.
Synthesis of the substituted trans-2-imidazoyl-cycloalkanols
´
de Vicent Sos Baynat s/n, 12071 Castellon, Spain. E-mail: luiss@uji.es;
Fax: +34 964728214; Tel: +34 964728239
Firstly, the nucleophilic opening of cycloalkene oxides 1a–b
with different substituted imidazoles (2a–e) was performed
obtaining the corresponding racemic cyclopentanols 3a–e and
cyclohexanols 4a–e using refluxing 1,4-dioxane as solvent (Table 1).
b
´
´
´
Departamento de Quımica Organica e Inorganica, Universidad de Oviedo, Oviedo,
Spain. E-mail: vgs@uniovi.es; Tel: +34 985103451
† Electronic supplementary information (ESI) available: Full characterization of
novel compounds and NMR spectra. See DOI: 10.1039/c3cy00107e
c
This journal is The Royal Society of Chemistry 2013
Catal. Sci. Technol.

View Article Online
Paper
Catalysis Science & Technology
Table 1 Synthesis of racemic alcohols 3a–e and 4a–e
lower reactivities, although maintaining high enantioselectivities,
were noticed for (4d) and (4e) having substituents close to the
alcohol group. An increase in the temperature to 45 1C was
required to achieve 50% conversion in 67 h for 4d (entries 7
and 8). Lower conversions were observed for the more sterically
demanding substrate 4e even at 60 1C (entries 9 and 10).
Similarly the five-membered ring imidazoles were efficiently
resolved using PSL-C Amano, CAL-B or PSL-C I, depending on
the substrate structure. Short reaction times and 30 1C were
appropriate for the non-substituted imidazole 3a or the 4-phenyl
derivative 3c (entries 11–13, 16 and 17) while slightly longer
times were needed for the 4-methylated compound 3b (entries 14
and 15). Best results for the 2-substituted analogues 3d and e
were attained at 60 1C and using CAL-B, providing in both cases
the (S,S)-alcohols in enantiomerically pure form (entries 18–21).
Entry
Oxide
Imidazole
t (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
18
24
23
24
23
24
23
24
97
94
88a
86a
89b
78b
50b
56b
62b
71b
71b
90b
Ion-pairing formation vs. H-bond interaction
In principle, these chiral imidazoles could form the corres-
ponding salts with (L)-proline by a simple acid–base reaction.
This was checked by adding a methanolic solution of the
corresponding imidazole to a solution containing one equivalent
a
b
Reaction performed with 2 M imidazole. Reaction performed with
5 M imidazole.
In all cases, the ring opening afforded exclusively the trans- of (L)-proline. After removing the solvent, the crude mixtures
alcohol isomers, the formation of the cis-analogues not being were analyzed by 1H-NMR, FT-IR ATR and DSC. The 1H-RMN did
observed. The most hindered imidazoles (R1 or R2 = Me, Ph) were not show any trend that could reveal the formation of the
less reactive than the unsubstituted ones (R1 and R2 = H). For corresponding imidazolium salt, which suggests that the sub-
that reason, more concentrated solutions (5 M) were used for the stituted imidazoles are not basic enough for this purpose. Only
substituted imidazoles 2b–e (in comparison to 2 M for 2a).
slight shifts were observed, in particular for the signal corres-
The effect of the steric congestion on the proximity of the ponding to the a-CH proton of the (L)-proline (see Fig. S1 at ESI†).
reactive nitrogen atom is especially remarkable in the case of For an equimolecular mixture of (L)-proline and 4d this signal is
2-phenylimidazole (2e) requiring 4 days to achieve high conversions shifted from 3.62 to 3.67 ppm. This indicates a certain degree of
of the corresponding racemic alcohols 3e and 4e (Table 1, entries 9 interaction between the imidazole and (L)-proline even when a
and 10). All the final products were isolated in high purity after polar solvent (DMSO) was used. The FT-IR ATR of the solid
flash chromatography and an additional washing of the resulting mixture also suggests the presence of some interaction between
colour solids with hot diethyl ether. For 4-methylimidazole (2b) two both components. Thus, for the imidazole:(L)-proline mixture, a
isomers were detected corresponding to the two possible nucleo- red-shift in the CQO stretching frequency (from 1550.5 to
philic attacks involving the non-equivalent nitrogen atoms of the 1557.7 cmꢁ1, see Fig. S2 at ESI†) is observed, accompanied by
imidazole ring, isolating 3b and 4b as a mixture of the 4-methyl and a reduction of the band intensity in comparison with the pure
the 5-methyl isomers in 4 : 1 and 7 : 1 ratio respectively.
(L)-proline. The H-bonded OH stretch also confirms this trend. In
For the enzymatic kinetic resolution of the corresponding the mixture, the intensity of the OH stretching band is reduced,
racemic alcohols, Candida antarctica lipase B (CAL-B) and being shifted from 3048.4 to 3061.9 cmꢁ1 suggesting a weaker
Pseudomonas cepacia lipase (PSL-C I, currently known as H-bond network than in pure (L)-proline (see Fig. S2 at ESI†).
Burkholderia cepacia lipase) were selected as the possible bio-
This situation is also supported by DSC studies of different
catalysts for the acetylation reaction. A three-fold excess of vinyl combinations of the imidazole 4a (mp = 88 1C) and (L)-proline
acetate (VinOAc, 7), a commonly employed activated ester for (mp = 222 1C). The results showed that the addition of imida-
the kinetic resolution of alcohols, was used as the acyl donor. zole resulted in dramatic reductions in the melting point of
Tetrahydrofuran, an organic solvent usually applied in lipase- (L)-proline (see Fig. S3 and Table S1 at ESI†). Thus, a mixture
catalyzed kinetic resolutions, was used as the solvent (Table 2). with only 0.17 molar equiv. of 4a led to a melting point
The asymmetric O-acylation of related six membered ring reduction of ca. 30 1C. For the 4a:(L)-proline equimolecular
alcohols has been previously reported using tert-butyl methyl mixture, the melting point was 168 1C, while the excess of 4a
ether (TBME), PSL-C from Amano Pharmaceuticals and at 45 1C (5 molar equiv., X4a = 0.83) further reduced the temperature to
yielding the acetate (R,R)-6a and the alcohol (S,S)-4a in enantiopure 155 1C (see Fig. S4 at ESI†). This behaviour is reminiscent of the
form and good yields (entries 1–4).12 Accordingly, PSL-C was one reported for salicylic acid–salicylate mixtures.14 The melting
selected for the biotransformation of the six-membered ring point of the imidazole is also affected. For the equimolecular
substituted imidazole derivatives (ꢀ)-4b–e. Optimal kinetic mixture, a reduction of the melting point from 88 1C to 68 1C
resolutions were attained for the 4-substituted derivatives (4b) was found (onset temperature, see Table S1 at ESI†). Hence,
and (4c) after 13 h at 30 1C (Table 2, entries 5 and 6). However, supramolecular interactions via hydrogen bonding between the
c
Catal. Sci. Technol.
This journal is The Royal Society of Chemistry 2013

View Article Online
Catalysis Science & Technology
Paper
Table 2 Lipase catalyzed kinetic resolution of racemic alcohols trans-3a–e and trans-4a–e
cb (%)
Ec
a
a
Entry
Alcohol
Enzyme
Solvent
T (1C)
t (h)
eeS (%)
eeP (%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4b
4c
4d
4d
4e
4e
3a
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
CAL-B
THF
THF
TBME
TBME
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
30
30
30
45
30
30
30
45
45
60
30
30
30
30
30
30
30
30
60
60
60
39
14
13
15
13
13
92
67
136
72
14
14
14
48
48
15
15
92
60
55
55
93
97
33
>99 (88)
95 (92)
99 (92)
92
99 (88)
23
98
98
>99
>99 (91)
>99 (91)
>99 (94)
>99
>99 (91)
>99
49
48
25
50
48
50
48
50
19
21
50
49
50
50
49
50
43
38
51
51
38
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
PSL-C Amano
PSL-C Amano
PSL-C Amano
PSL-C Amano
PSL-C Amano
PSL-C Amano
PSL-C Amano
PSL-C Amano
PSL-C Amano
CAL-B
PSL-C Amano
PSL-C I
CAL-B
PSL-C I
CAL-B
9
10
11
12
13
14
15
16
17
18
19
20
21
26
>99
99 (92)
97 (88)
>99 (92)
99 (92)
94 (88)
>99 (80)
74 (90)
66 (73)
>99 (94)
>99 (90)
60 (90)
>99 (91)
>99 (91)
>99 (94)
>99 (94)
>99 (94)
>99 (93)
>99 (96)
99 (84)
95 (91)
96 (91)
>99 (87)
PSL-C I
CAL-B
CAL-B
CAL-B
PSL-C I
a
b
Enantiomeric excesses determined by HPLC; isolated yields in brackets refer to the corresponding conversion value. Conversion values:
c = eeS/(eeS + eeP). Enantiomeric ratio: E = ln[(1 ꢁ c) ꢂ (1 ꢁ eeP)]/ln[(1 ꢁ c) ꢂ (1 + eeP)].13
c
carboxyl group of proline and both nitrogen atoms (preferentially 40 mol% of proline, and at a 0.14 M concentration of aldehyde
the unsubstituted one) and the –OH group of the imidazole seem in the presence and absence of one equivalent of the imidazole
to be established and one possible model is shown in Fig. 1. Such 4a. Fig. 2 depicts the profile of aldol formed vs. reaction time
interactions should be weaker than those found in pure (L)-proline for the reaction with and without 4a. It seems clear that
but compete with proline–proline interactions reducing the the presence of 4a as an additive substantially increases the
melting point in the solid mixtures. Similar trends can be found reaction rate. Thus, after four hours ca. 90% of aldol is obtained
for mixtures of (L)-proline with other imidazoles (see Table S2 at in the presence of 4a, while the reaction catalyzed just by
ESI†). Thus, such proline–chiral imidazole interactions can (L)-proline led to less than 20% yield. Therefore, the additive
provide an opportunity for the fine tuning of the catalytic has a significant positive effect on the activity. It is worth
performance of (L)-proline.15
mentioning that the (L)-proline presents a low solubility in
acetone. Indeed, the NMR spectrum indicates that only around
10% of added (L)-proline is solubilised in acetone, leading to a
5.7 mM concentration instead of the expected 57 mM. The
presence of 4a produces a twofold enhancement of the solubility
of (L)-proline in acetone (from 5.7 to 11.4 mM). Thus, as the
imidazole is completely soluble, the actual molar ratio of
4a :(L)-proline in the solution is 5 : 1, even when an equimolecular
solid mixture of both of them was added to the reaction.
The impact of substituted trans-2-imidazoyl-cycloalkanols on
the (L)-proline catalytic efficiency
In order to elucidate the potential use of trans-2-imidazoyl-
cycloalkanols as additives for aldol reactions catalyzed by
(L)-proline, the neat reaction between p-nitrobenzaldehyde
and acetone was studied inside an NMR tube using deuterated
acetone. Initially, the reactions were performed at 25 1C with a
Important changes in the enantioselectivity of the reaction
were also produced by the presence of imidazoles as co-catalysts.
In order to identify the structural factors affecting the stereo-
selectivity of the process the model reaction was carried out with
an equivalent amount of different substituted imidazoles. The
results are summarized in Table 3.
In the case of 4a, the corresponding aldol was obtained with
Fig. 1 Possible hydrogen bonding interactions for the imidazole–proline system. only a moderate enantiomeric excess (31% ee, Table 3, entry 3).
c
This journal is The Royal Society of Chemistry 2013
Catal. Sci. Technol.

View Article Online
Paper
Catalysis Science & Technology
corresponding substituted cyclopentyl imidazoles were tested
as co-catalysts. The acetylation of the hydroxyl group resulted in
higher asymmetric inductions (65% ee for (R,R)-trans-b-OAc-
cyclohexylimidazole and B50% ee for (S,S)-trans-b-OH-cyclo-
hexylimidazole, Table 3, entries 4 and 5). The same trend was
observed for imidazole derivatives methylated at C2 (55% ee for
the acetylated compound vs. 37% ee for the alcohol, Table 3,
entries 6 and 7). Note that replacement of the proton by a
methyl group at C2 reduced in both cases the asymmetric
induction (Table 3, entry 4 vs. 6 and entry 5 vs. 7). The presence
of a relatively bulky group in C4, such as phenyl, did not result
in a significant change in the enantioselectivity of the aldol
(Table 3, entries 4 vs. 8). Thus, a greater asymmetric induction
was achieved with imidazoles not substituted at the C2 position
and the acetylated hydroxyl group. Indeed, the level of enantio-
selection achieved in the presence of the additive, especially for
5a, can be as good as that found for the reaction catalyzed by
(L)-proline in the absence of any imidazole (entry 1, Table 2) but
with the enhancement in catalytic activity.
Fig. 2 Kinetic profile for the aldol reaction (a) red triangles: 1 : 1 ratio 4a :
(L)-proline; (b) black dots: absence of 4a. 1 : 0.4 RCHO : cat ratio, 25 1C, 1.36 M in
d6-acetone.
When just N-methyl imidazole was used, the ee found was
higher than that obtained for 4a and similar to that of the
reference system (50% ee, Table 3, entry 2).
As the enantioselectivity achieved by cyclopentyl imidazole
derivatives was higher (51% ee for 3a) than that for cyclohexyl
derivatives (31% ee for 4a, Table 3, entries 3 and 4) the
Additionally, the same imidazole:(L)-proline mixtures were also
tested for the neat reaction between p-nitrobenzaldehyde and
cyclohexanone. The results obtained are summarized in Table 4.
Table 3 Aldol reaction between p-nitrobenzaldehyde and acetonea
Table 4 Aldol reaction between p-nitrobenzaldehyde and cyclohexanonea
Entry Imidazole derivative Conversionb (%) Selectivityc (%) eed (%)
1
2
—
>99
>99
99
99
65
50
Imidazole
Entry derivative
Selectivity
Yieldb (%) anti : sync (%) eeanti (%) eesyn (%)
g
d
1
2
—
99
98
50 : 50
70 : 30
7
97f
60f
3
4
5
>99
>99
>99
90
95
99
31
51
65
65
3
4
5
99
99
99
70 : 30
70 : 30
69 : 31
78
72
79
65f
41f
13f
6
7
>99
90
37
6
99
99
67 : 33
67 : 33
77
84
23e
84f
>99
>99
99
98
55
53
7
8
a
RCHO : cyclohexanone : cat 1 : 10 : 0.4, (1 : 1) imidazole-(L)-proline, at
a
RCHO : acetone : complex (imidazole-(L)-proline) 1 : 10 : 0.4, at room
room temperature for 24 hours and aldehyde concentration: 0.96 M.
b
c
Yield calculated by 1H-NMR in the crude of the reaction. Selectivity
temperature for 24 hours; imidazole-(L)-proline molar ratio 1 : 1 and
b
1
calculated by 1H-NMR in the crude of the reaction for the anti
aldehyde concentration 1.36 M. Conversion calculated by H-NMR in
the crude of the reaction. Selectivity calculated by 1H-NMR in the
c
d
diastereomer. Enantiomeric excess calculated by HPLC for each
crude of the reaction. Selectivity refers to the ratio between aldol
products and side products, being those dehydration products or
formed through parasite reactions (ref. 16). Enantiomeric excess
calculated by HPLC for the enantiomer R (major peak) [ee = (peak area
(R) ꢁ peak area (S)) ꢂ 100/total area (R + S)].
diastereoisomer [ee = (major peak area ꢁ minor peak area) ꢂ 100/total
e
area]. First major peak of the two peaks of syn diastereoisomers in the
d
f
HPLC. Second major peak of the two peaks of syn diastereoisomers in
g
the HPLC. Enantiomeric excess calculated by HPLC for the enantio-
mer 20R,10S (major peak) of the anti diastereoisomer.
c
Catal. Sci. Technol.
This journal is The Royal Society of Chemistry 2013

View Article Online
Catalysis Science & Technology
Paper
All mixtures tested were active, leading to the corresponding aldol NMR, DEPT, and 1H–13C heteronuclear experiments were
with excellent yields. The diastereoselectivity of the process was performed using AV-300 (1H, 300.13 MHz and 13C, 75.5 MHz),
similar for the different imidazoles tested with an anti :syn ratio of DPX-300 (1H, 300.13 MHz and 13C, 75.5 MHz) or AV-400
70 : 30. These diastereoselectivity values are higher than those for (L)- (1H, 400.13 MHz and 13C, 100.6 MHz) Bruker spectrometers or
proline alone under the same experimental conditions (50 : 50 Varian INOVA 500. The chemical shifts are given in delta (d)
anti :syn). In terms of enantioselectivity, similar trends to those values and the coupling constants (J) in Hertz (Hz). A HP1100
described above for the reaction with acetone were obtained in most chromatograph mass detector was used to record mass spectra
cases. In general, acetylated derivatives produced an asymmetric experiments (MS) through APCI+ or ESI+ experiments. Measure-
induction higher than the non-acetylated ones (Table 4, entry 3 vs. 4 ment of the optical rotation was done in a Perkin-Elmer 241
and entry 5 vs. 6). The methylation of the C2 position is reflected in a polarimeter.
reduction of the enantioselectivity for the syn aldol, keeping it at a
General procedure for the synthesis of racemic alcohols
level similar to that of the anti aldol. This reduction in enantios-
electivity, in the case of the acetylated co-catalysts, was about 50%.
Noteworthily, for the C2 methylated imidazoles a topicity inversion
could be observed when comparing the acetylated and non-
acetylated derivatives (Table 4, entry 4 vs. 6). For this reaction, the
presence of a 4-phenyl group at the imidazole ring slightly improved
the enantiomeric excess obtained, reaching a 84% ee for both the
anti and syn isomers. Hence, all results show that the substitution
pattern of the imidazole used as the additive appears to be essential
to determine the asymmetric induction.
A solution of oxide 1a–b (15.63 mmol) and the corresponding
imidazole derivative 2a–e (12.50 mmol) in 1,4-dioxane (2.50 mL)
was stirred at 100 1C for 18–97 h and then the mixture was
cooled to room temperature. After this time, the solvent was
evaporated under reduced pressure and the resulting crude
purified by flash chromatography on silica gel (10% MeOH/
CH2Cl2) yielding (ꢀ)-trans-3a–e or (ꢀ)-trans-4a–e (50–90%) as
white solids. For additional data see Table 1.
General procedure for the synthesis of racemic acetates
Conclusions
To a solution of (ꢀ)-trans-3a–b (0.32 mmol) or (ꢀ)-trans-4a–b in
dry CH2Cl2 (3.2 mL), Et3N (133 mL, 0.95 mmol), DMAP (12.8 mg,
0.10 mmol) and Ac2O (60 mL, 0.62 mmol) were successively
added under a nitrogen atmosphere. The reaction was stirred at
room temperature for 4 h until complete consumption of the
starting material, and then the solvent was evaporated under
reduced pressure. The reaction crude was purified by flash
chromatography on silica gel (5% MeOH/CHCl3) yielding
(ꢀ)-trans-5a–e and trans-6a–d as pale yellow oils, or trans-6e
as a white solid (78–98% yield).
In summary, we have shown that enantiopure substituted imida-
zoles obtained by enzymatic kinetic resolution can be promising
candidates as co-catalysts for aldol reactions catalysed by (L)-proline.
These additives seem to form supramolecular complexes with the
catalyst through the formation of H-bonds, leading to a significant
improvement in both the reaction rates and the selectivity of the
reaction. The stereoselectivity of the process is highly influenced by
the structural parameters of the imidazole. The systems tested reveal
the importance of the substitution pattern at the C2 position, the
size of the cycloalkyl ring attached to one of the nitrogen atoms of
the imidazole and the presence of a hydroxyl group or its acetylated
counterpart as key parameters to optimize the enantioselectivity. We
are currently exploring other classes of azole-based systems that
can benefit from being programmed to interact as complementary
co-catalysts and will report in due course.
General procedure for the enzymatic kinetic resolution of
imidazole derivatives
To a suspension of racemic alcohol trans-3a–e or trans-4a–e
(0.60 mmol) and the corresponding enzyme (CAL-B or PSL-C I
in 1 : 1 weight ratio relative to the alcohol) in dry THF (6.0 mL),
vinyl acetate (166 mL, 1.80 mmol) was added under a nitrogen
atmosphere at 30–60 1C. The reaction was shaken for the
appropriate time at different temperatures and 250 rpm.
Aliquots were regularly analyzed by HPLC until around 50%
conversion was reached. The reaction was stopped and the
enzyme filtered off using CH2Cl2 (3 ꢂ 5 mL), the solvent
evaporated under reduced pressure and the reaction crude
purified by flash chromatography on silica gel (5–10% MeOH/
CHCl3) affording the corresponding optically enriched acetates
and alcohols. For additional data see Table 2.
Experimental section
Candida antarctica lipase type B (CAL-B, Novozyme 435, 7300
PLU gꢁ1) was a gift from Novozymes. Pseudomonas cepacia
lipase was purchased from Amano Pharmaceuticals (PSL-C
Amano, 1019 U gꢁ1) or Sigma-Aldrich (PSL-C I, 1638 U gꢁ1).
All other reagents were purchased from Aldrich and used
without further purification. Solvents were distilled over an
adequate desiccant under nitrogen. Flash chromatography was
performed using silica gel 60 (230–240 mesh). High performance
liquid chromatography (HPLC) analyses were carried out at 20 1C
in a Hewlett Packard 1100 chromatograph under the conditions
General procedure for the formation of the imidazole:(L)-
proline complex
specified for each substrate and with UV monitoring at 210 nm To a solution of the corresponding substituted imidazole
or 254 nm. IR spectra were recorded either on NaCl plates or KBr (0.27 mmol) in MeOH (5 mL) (L)-proline (32.1 mg, 0.27 mmol)
pellets in a Perkin-Elmer 1720-X FT or on a MIRacle Single was added. The resulting mixture was stirred at room tempera-
Reflection Diamond/ZnSe ATR in a Jasco FT-IR 6200. 1H, 13C ture for 24 h. After this time, the solvent was removed by
c
This journal is The Royal Society of Chemistry 2013
Catal. Sci. Technol.

View Article Online
Paper
Catalysis Science & Technology
4 S. V. Ley, Asymmetric Organocatalysis, in Asymmetric
synthesis, ed. M. Christmann and S. Braese, Wiley-VCH,
Weinheim, Germany, 2008, pp. 201–206.
distillation under reduced pressure to obtain the corres-
ponding complex.
General procedure for the aldol reaction
´
´
5 G. Guillena, C. Najera and D. J. Ramon, Tetrahedron:
Asymmetry, 2007, 18, 2249–2293; M. Gruttadauria, F. Gialcone
and R. Noto, Chem. Soc. Rev., 2008, 37, 1666–1688;
J. G. Hernandez and E. Juaristi, Chem. Commun., 2012, 48,
5396–5409.
Over a mixture of the corresponding imidazole : (L)-proline
complex (1 : 1) (0.4 mmol) and acetone or cyclohexanone
(10 mmol), p-nitrobenzaldehyde (1 mmol) was added. The
resulting mixture was stirred for 24 h at room temperature,
following the reaction by TLC (33% EtOAc/hexane). After that
time, chloroform (10 mL) was added and the mixture was
washed with deionized water (3 ꢂ 5 mL). The organic phase
was dried with anhydrous magnesium sulphate and the solvent
evaporated under reduced pressure. The resulting crude was
purified by flash chromatography on silica gel (33% EtOAc/
hexane).
6 S. P. Mathew, M. Klussmann, H. Iwamura, D. H. Wells,
A. Armstrong and D. G. Blackmond, Chem. Commun., 2006,
4291–4293; N. Zotova, A. Moran, A. Armstrong and
D. G. Blackmond, Adv. Synth. Catal., 2009, 351, 2765–2769.
7 Y. Zhou and Z. Shan, J. Org. Chem., 2006, 71, 9510–9512;
C.-S. Da, L.-P. Che, Q.-P. Guo, F.-C. Wu, X. Ma and Y.-N. Jia,
J. Org. Chem., 2009, 74, 2541–2546.
¨
8 O. Reis, S. Eymur, B. Reis and A. S. Demir, Chem. Commun.,
´
2009, 1088–1090; X. Companyo, G. Valero, L. Crovetto,
4-Hydroxy-4-(4-nitrophenyl)butan-2-one
A. Moyano and R. Rios, Chem.–Eur. J., 2009, 15,
6564–6568; S. L. Poe, A. R. Bogdan, B. P. Mason,
J. L. Steinbacher, S. M. Opalka and D. T. McQuade, J. Org.
1H-NMR (CDCl3, 500 MHz): d 2.10 (s, 3H, CH3), 2.78 (dd, 2H, J =
3.3, 6.6 Hz, CH2), 3.94 (s, 1H, OH), 5.17 (dt, 1H, J = 3.8, 7.7 Hz,
CH), 7.44 (d, 2H, Ph), 8.02 (d, 2H, J = 8.9 Hz, Ph). Rf: 0.25 (33%
EtOAc/hexane). HPLC: 36.2 min (R) and 41.1 min (S) (Chiralcel
OJ, Hex/IPA (90 : 10), flow: 0.75 mL minꢁ1, T: 30 1C, l: 254 nm).
´
Chem., 2009, 74, 1574–1580; N. El-Hamdouni, X. Companyo,
R. Rios and A. Moyano, Chem.–Eur. J., 2010, 16, 1142–1148.
´
˜
´
9 A. Martınez-Castaneda, B. Poladura, H. Rodrıguez-Solla,
´
C. Concellon and V. Amo, Org. Lett., 2011, 13, 3032–3035;
2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one
´
˜
´
A. Martınez-Castaneda, B. Poladura, H. Rodrıguez-Solla,
1H-NMR (CDCl3, 500 MHz): d 1.32–1.78 (m, 5H), 2.26–2.53
(m, 4H), 4.02 (s, 1H, OH), 4.83 (d, 1H, J = 8.3 Hz, CH, anti), 5.41
(s, 1H, CH, syn), 7.44 (d, 2H, J = 8.5 Hz, Ph), 8.13 (d, 1H, J = 8.5 Hz,
Ph). Rf: 0.27 (33% EtOAc/hexane). HPLC: 16.2 min and 20.6 min
(syn); 22.3 min (2S,10R) and 29.6 min (2R,10S) (anti) (Chiralpak AD,
Hex/IPA (90 : 10), flow: 1 mL minꢁ1, T: 30 1C, l: 254 nm).
´
C. Concellon and V. Amo, Chem.–Eur. J., 2012, 18,
5188–5190.
10 D. G. Blackmond, A. Moran, M. Hughes and A. Armstrong,
J. Am. Chem. Soc., 2010, 132, 7598–7599; M. B. Schmid,
K. Zeitler and R. M. Gschwind, Chem.–Eur. J., 2012, 18,
3362–3370.
11 A. I. Nyberg, A. Usano and P. M. Pihko, Synlett, 2004,
1891–1896; D. E. Ward and V. Jheengut, Tetrahedron Lett.,
2004, 45, 8347–8350; M. Amedjkouh, Tetrahedron: Asymme-
try, 2005, 16, 1411–1414; P. M. Pihko, P. M. Laurikanien,
A. Usano, A. I. Nyberg and J. A. Kaavi, Tetrahedron, 2006, 62,
317–328; N. Zotova, A. Franzke, A. Armstrong and
D. G. Blackmond, J. Am. Chem. Soc., 2007, 129, 15100–15101.
Acknowledgements
We thank Novozymes for the generous gift of CAL-B (Novozyme
435). This work was supported by GV-PROMETEO/2012/020,
Bancaja P1-1B-2009-58, CTQ-2011-28903 and CTQ-2011-24237.
Cooperation of the SCIC of the UJI for instrumental analyses is
acknowledged.
´
´
´
´
12 E. Busto, V. Gotor-Fernandez, N. Rıos-Lombardıa, E. Garcıa-
´
´
Verdugo, I. Alfonso, S. Garcıa-Granda, A. Menendez-
´
Velazquez, M. I. Burguete, S. V. Luis and V. Gotor, Tetrahedron
Notes and references
´
´
Lett., 2007, 48, 5251–5354; N. Rıos-Lombardıa, E. Busto,
´ ´
V. Gotor-Fernandez, V. Gotor, R. Porcar, E. Garcıa-Verdugo,
1 For reviews on asymmetric organocatalysis: H. Pellissier,
Tetrahedron, 2007, 63, 9267–9331; M. J. Gaunt, C. C. C.
Johansson, A. McNally and N. T. Vo, Drug Discovery Today,
´
´
S. V. Luis, I. Alfonso, S. Garcıa-Granda and A. Menendez-
´
Velazquez, Chem.–Eur. J., 2010, 16, 838–847.
2007, 12, 8–27; A. Dondoni and A. Massi, Angew. Chem., Int. 13 C. S. Chen, Y. Fujimoto, G. Girdaukas and C. J. Sih, J. Am.
Ed., 2008, 47, 4638–4660; P. Melchiorre, M. Marigo, Chem. Soc., 1982, 102, 7294–7299.
A. Carlone and G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 14 N. S. Golubev, S. N. Smirnov, P. Schah-Mohammedi,
6138–6171; R. C. Wende and P. R. Schreiner, Green Chem.,
2012, 14, 1821–1849.
2 S. K. Panday, Tetrahedron: Asymmetry, 2011, 22, 1817–1847;
I. G. Shenderovich, G. S. Denisov, V. A. Gindin and
H. H. Limbach, Russ. J. Gen. Chem., 1997, 67, 1082
(Zh. Obshch. Khim., 1997, 67, 1150).
´
S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. 15 X. Companyo, M. Viciano and R. Rios, Mini-Rev. Org. Chem.,
Rev., 2007, 107, 5471–5569. 2010, 7, 1–9.
3 V. Bisau, A. Bisau and V. K. Singh, Tetrahedron, 2012, 68, 16 N. Zotova, A. Franzke, A. Armstrong and D. G. Blackmond,
4541–4580.
J. Am. Chem. Soc., 2007, 129, 15100–15101.
c
Catal. Sci. Technol.
This journal is The Royal Society of Chemistry 2013