Evaluation of 6-APA as a new organocatalyst for a direct cross-aldol reaction

Article abstract of DOI:10.1002/ejoc.200900181

6-Aminopenicillanic acid (6-APA) and two of its derivatives, 6-APA benzyl ester (6-APA-OBn) and Penicillin G (PenG), have been evaluated as catalysts for use in direct cross-aldol reactions in different solvents and. mixtures. The effects of catalyst load

Full text of DOI:10.1002/ejoc.200900181

FULL PAPER
DOI: 10.1002/ejoc.200900181
Evaluation of 6-APA as a New Organocatalyst for a Direct Cross-Aldol
Reaction
Enrico Emer,[a] Paola Galletti,*[a] and Daria Giacomini*[a]
Keywords: Asymmetric catalysis / Aldol reactions / Penicillins / Organocatalysis
6-Aminopenicillanic acid (6-APA) and two of its derivatives,
6-APA benzyl ester (6-APA-OBn) and Penicillin G (PenG),
have been evaluated as catalysts for use in direct cross-aldol
reactions in different solvents and mixtures. The effects of
catalyst loading, reaction time, pH and temperature on the
yield and stereoselectivity have been studied. 6-APA proved
to be an effective catalyst in terms of yield for the reaction
between cyclohexanone and p-nitrobenzaldehyde, espe-
cially in neat conditions. The stereoselectivity of the reaction
was conditioned by the presence of two competing mecha-
nisms: one an imine–enamine pathway and the other a
Brønsted acid catalysis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The organocatalysed aldol reaction has been the object
of extraordinary efforts in recent years.[1] Many kinds of
small organic molecules, such as amines,[2] proline[3] and Figure 1. 6-APA and derivatives evaluated as catalyst.
other amino acids[4] and small peptides,[5] have been used
as catalysts to promote asymmetric C–C bond formation.
6-Aminopenicillanic acid (6-APA)[6] is a particular kind
of amino acid produced by several species of Penicillium
Results and Discussion
and Aspergillus and it is the active nucleus common to all
penicillins. 6-APA is the basic material used for the indus-
trial production of antibiotics. The year 2007 marked the
As a model reaction, we explored the aldol condensation
between cyclohexanone and p-nitrobenzaldehyde. In a pre-
liminary combinatorial screening we tested some polar
50th anniversary of the discovery of 6-APA, which made
aprotic solvents and mixtures with water using 6-APA
possible the development of semi-synthetic penicillins that
(30 mol-% with respect to the aldehyde) as the catalyst (see
have become one of the most important groups of antibiot-
Table 1). Products were detected in minimal amounts except
ics in clinical practice. 6-APA is a very cheap, easily avail-
for when the reaction was conducted in water, in which case
able, enantiopure chiral compound. It is industrially pro-
a yield of 36% was obtained. Notably, better yields were
duced either by chemical or enzymatic deacylation using
obtained when the reaction was conducted in solvent-free
penicillin amidase from Penicillin G or V, which are in turn
conditions in an excess of ketone: complete conversion was
achieved and syn/anti products were obtained in 86% yield
with a 23:77 diastereomeric ratio in favour of the anti iso-
mer. In this case, the addition of 6-APA seemed to improve
efficiently obtained from biotechnological processes.[7] For
many years we have been working on the synthesis of biolo-
gically active β-lactam derivatives and on their use as syn-
thons.[8] Herein, we present our results on the evaluation of
the homogeneity of the reaction mixture.
6-APA and two of its derivatives, 6-APA benzyl ester (6-
These results prompted us to undertake a more detailed
APA-OBn) and Penicillin G (PenG; see Figure 1), as cata-
study of the 6-APA-catalysed aldol reaction in water and
lysts in direct cross-aldol reactions. To the best of our
in solvent-free conditions, considering the influence of the
knowledge, this is the first application of penicillins as or-
amount of catalyst, time, pH and temperature on the yield
and stereoselectivity. The course of the reaction at different
ganocatalysts in asymmetric synthesis.
temperatures and with different amounts of catalyst was
carefully monitored by HPLC and 1H NMR analysis at
various reaction times (Table 2 and Figure 2).
[a] Department of Chemistry “G. Ciamician”, University of Bolo-
gna,
via Selmi 2, 40126 Bologna, Italy
Fax: +39-051-2099456
E-mail: paola.galletti@unibo.it
daria.giacomini@unibo.it
As expected, in the absence of the catalyst the reaction
did not proceed. When 6-APA was used in a stoichiometric
amount, there was complete conversion into the products;
Eur. J. Org. Chem. 2009, 3155–3160
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3155

E. Emer, P. Galletti, D. Giacomini
FULL PAPER
Table 1. Aldol condensation between cyclohexanone and p-ni- pend on the amount of 6-APA, but the enantiomeric excess
trobenzaldehyde catalysed by 6-APA in different solvents.[a]
varied with the best values for both the syn and anti dia-
stereoisomers being obtained with 10 mol-% 6-APA. Note
that at low conversion, the syn isomer was the preferred
diastereoisomer, but its relative amount progressively di-
minished because of the concomitant formation of enone 2,
and ultimately the anti diastereoisomer predominated on
disappearance of the aldehyde (Table 2, entries 5, 8 and 10).
Even at low temperatures the preferred diastereoisomer was
the syn isomer. Thus, the syn isomer can be considered the
kinetically controlled diastereoisomer.
Entry
Solvent
% Yield of 1a + 1b
syn/anti[b]
By monitoring the ongoing reaction, we noticed the pres-
ence of transient byproducts A and AЈ. They appeared as a
double peak in the HPLC analysis, and their amount de-
creased as the starting aldehyde was consumed. The 1H
NMR spectra of the crude products at lower aldehyde con-
versions showed the presence of two signal pairs at 6.53,
6.41, 5.76, and 5.07 ppm, which suggests the presence of at
least two stereoisomers of the hemiacetal structure A de-
picted in Figure 2. Attempts to isolate the products by flash
chromatography failed, but identical HPLC and NMR sig-
nals were obtained by mixing the final aldols 1a,b and the
starting aldehyde, which supports the proposed structure.
Mass spectra consistent with these findings were obtained
in negative ionization mode (ESI HPLC–MS): the peak at
m/z = 435 was attributed to the [M – H + 2H2O]– ion. The
same typical ionization cluster was recognized in the MS of
aldols 1a,b (peak at m/z = 284). To the best of our knowl-
edge, this is the first case in which these kinds of byproducts
have been reported. To trace the presence of any other inter-
mediates, imines of 6-APA with the aldehyde and cyclo-
hexanone were prepared for comparison, but no iminic-en-
aminic intermediates formed between 6-APA and the alde-
hyde or ketone were observed.
1
2
3
4
5
6
7
8
9
THF/H2O (1:1)
THF
DMF/H2O (1:1)
DMF
DMSO/H2O (1:1)
DMSO
H2O
7
13
13
12
7
7
36
4
57:43
66:34
51:49
58:42
50:50
56:44
58:42
54:46
23:77
BMIM NTf2
Neat[c]
86
[a] Experimental conditions: p-nitrobenzaldehyde (0.5 mmol), cy-
clohexanone (1.5 mmol), 6-APA (0.15 mmol, 30 mol-%), solvent
(2 mL), T = 27 °C, time = 84 h. [b] The syn/anti ratio was evaluated
by HPLC analysis. [c] In this case the cyclohexanone was used in
excess: p-nitrobenzaldehyde (0.5 mmol) and cyclohexanone
(2.5 mmol).
by lowering the amount of catalyst, good conversions could
be still obtained by extending the reaction times (Table 2,
entries 8, 10 and 15). From 100 to 10 mol-% catalyst, the
anti diastereoisomer was preferentially formed, even if with
a low diastereoselectivity (Table 2, entries 2, 5, 8 and 10).
In these cases, we also recorded the presence of variable
amounts of the dehydrated aldol adduct 2 as a byproduct.[9]
Some experiments were conducted to examine the scope
The distribution between aldols and enone 2 did not de- of the 6-APA catalytic system in neat conditions, and the
Table 2. Influence of amount of catalyst, time and temperature on the aldol condensation between cyclohexanone and p-nitrobenzaldehyde
catalysed by 6-APA in “neat” conditions.[a]
Entry
Cat. [mol-%]
T [°C]
t [h]
% Yield
syn/anti
% eesyn
% eeanti
1a + 1b
2
A + AЈ
1
2
3
4
5
6
7
8
–
100
30
30
30
20
20
20
10
10
5
5
5
5
5
10
10
27
27
27
27
27
27
27
27
27
27
27
27
27
27
27
0
96
24
17
25
58
17
41
96
56
96
21
40
64
88
97
117
243
–
–
10
1
4
13
–
5
12
5
15
1
3
–
3
33
16
–
8
16
2
–
–
34
–
22
87
67
74
87
33
79
85
76
85
22
34
48
57
67
32
68
32:68
72:28
66:34
23:77
75:25
52:48
30:70
51:49
33:67
72:28
69:31
65:35
61:39
58:42
78:22
78:22
51
16
46
53
29
59
9
5
–
10
11
12
13
14
15
16
17
13
20
34
14
10
–
6
10
10
–
18
59
36
60
0
–
–
[a] Experimental conditions: p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (2.5 mmol). The syn/anti ratio and ee were determined by
HPLC.
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Eur. J. Org. Chem. 2009, 3155–3160

6-APA as Organocatalyst for a Direct Cross-Aldol Reaction
1
Figure 2. HPLC–MS chromatogram (mass spectra in negative ionization mode) and H NMR (200 MHz) spectrum of a typical reaction
mixture.
results are summarized in Table 3. It appears that electron- of product yields, diastereoselectivity and enantioselectivity
poor aromatic aldehydes are better substrates than electron- for entries 1–7 are presented in Figure 3 as a function of
rich ones, but the stereoselectivity is poor.
pH. The expected pH-dependent distribution of the 6-APA
microspecies is also reported.
Table 3. Aldol condensations between cyclohexanone and aromatic
aldehydes catalysed by 10 mol-% 6-APA.[a]
Entry
R
Prod. t [h] % Yield syn/anti % eesyn % eeanti
1
2
3
4
5
pCNC6H5
pClC6H5
C6H5
pCH3OC6H5 6a,b
C6F5 7a,b
3a,b
4a,b
5a,b
72
162
76
90
48
82[b]
61
43
traces
86
62:38
54:46
57:43
–
23
20
11
–
20
21
19
–
51:49
18
13
[a] Experimental conditions: aldehyde (0.5 mmol), cyclohexanone
(2.5 mmol), 6-APA (0.05 mmol; 10 mol-%), T = 27 °C. [b] With this
aldehyde, enone and byproducts were detected.
Figure 3. pH-dependent distribution of the three major species of
6-APA (cationic, zwitterionic and anionic): aldol yields (᭹), anti %
(∆), syn % (᭡), eeanti (᭿) and eesyn (ᮀ) data as function of aqueous
buffer pH.
6-APA can be considered a sort of dipeptide with ter-
minal acid–base functionalities. It is possible to calculate
the pH-dependent distribution of the protonation of 6-APA
Conversions in the range of pH 1.9–4.8 were lower than
from the constants pK1 = 2.5 and pK2 = 4.75, which are those obtained in neat conditions, whereas at higher pH we
unusually low compared with values for α-amino acids.[10] observed higher yields. The diastereoselectivity was almost
Site-specific protonation of the amine and carboxylate constant in the pH range 2–5 with a predominance of the
groups gives rise to a set of four microspecies: anionic, cat- syn aldol. In this respect, 6-APA behaves in water like pri-
ionic, uncharged and zwitterionic. It has been found that mary amines or some reduced dipeptides, which catalyse
for 6-APA, the zwitterionic species dominates the un- the direct asymmetric aldol reaction with syn selectivity.[12]
charged form by a factor of 110.[11] Thus, only three micro- For pH values higher than 7, the diastereomeric ratio was
species need be considered. To explore the influence of pH, strongly affected by the concomitant elimination reaction,
the reaction was performed in “in water” conditions, buff- which eroded the syn aldol. The enantioselectivity was al-
ering the pH in the range 1.9–8.2, which favours the pres- ways low and reached its highest value for the anti dia-
ence of the cationic, zwitterionic or anionic form (Table 4, stereoisomer at pH 3.6, at which pH the zwitterionic form
entries 1–7), and in “on water” conditions, performing the is predominant, whereas for the syn diastereoisomer the ee
reaction in the presence of 5 equiv. of ketone and a small was almost constant in the range of pH 1.9–3.6. Thus, for
amount of water (50 µL; Table 4, entries 8 and 9). The plots both the syn and anti isomers, the ee is higher in the pres-
Eur. J. Org. Chem. 2009, 3155–3160
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3157

E. Emer, P. Galletti, D. Giacomini
FULL PAPER
Table 4. Influence of pH and the amount of water present in the aldol condensation between cyclohexanone and p-nitrobenzaldehyde
catalysed by 6-APA.[a]
Entry
pH[b]
Water
t [h]
% Yield
1a + 1b
syn/anti
% eesyn
% eeanti
2
[c]
1
2
3
4
5
6
7
8
9
–
2 mL
2 mL
2 mL
2 mL
2 mL
2 mL
2 mL
50 µL
50 µL
70
64
64
66
56
56
56
138
97
36
26
19
24
22
61
79
76
73
–
1
1
1
1
31
7
14
20
58:42
71:29
69:31
64:36
64:36
52:48
33:68
32:68
38:62
9
18
17
15
8
7
1
12
18
14
32
18
8
6
18
20
1.9
2.5
3.6
4.8
7.0
8.2
[c]
–
36
31
2.1
[a] Experimental conditions (entries 1–7): p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (1.5 mmol), 6-APA (30 mol-%), aqueous buffer
(2 mL), T = 27 °C. Experimental conditions (entries 8 and 9): p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (2.5 mmol), 6-APA (10 mol-
%), T = 27 °C. [b] Buffers: AcOH/AcONa: pH 1.9; Na3PO4/citric acid: pH 2.5; citric acid/sodium citrate: pH 3.6 and 4.0; KH2PO4/
Na2HPO4: pH 7; boric acid/borax: pH 8.2. [c] No buffer.
ence of the cationic form of 6-APA. From these data it ap- mer (Table 5, entry 3). By using the Penicillin G potassium
pears that 6-APA is catalytically active in its cationic or salt, just traces of aldols could be detected (entry 2), which
zwitterionic form in the pH range 2–5, whereas at pH 7 and indicates that the carboxylic group must be protonated to
8 it is more likely that the reaction follows a general base exert catalytic activity. To force the presence of the proton-
catalysis mechanism. When the water content was lowered ated carboxylic group, we added two acid additives, benzoic
(Table 4, entries 8 and 9), the yields remained good, al- acid (pKa = 4.21) and/or trifluoroacetic acid (pKa = 0.3).
though higher amounts of elimination product 2 were ob- Unfortunately, the stereoselectivity did not improve, espe-
tained, thus giving rise to predominantly the anti isomer; cially when CF3COOH, which catalyses the achiral aldol
the enantiomeric excesses were better, but they still did not condensation by itself to some extent, was used (Table 5,
reach those obtained in neat conditions.
entries 6–8 and 10).
The enamine mechanism is largely accepted to be the
Proline is considered a “bifunctional catalyst” in cross-
most important activation method in asymmetric organoca- aldol reactions, and a joint action of the two proximal func-
talysis with proline.[13] However, for a primary amino acid tional groups is proposed in some of the mechanistic mod-
promoted enamine catalysis, an efficient imine–enamine els: the secondary amine in the enamine formation and the
tautomerism is essential.[14] To verify the imine–enamine carboxylic acid in the hydrogen-bond activation of the ac-
mechanism and to clarify the catalytic role of the amino ceptor carbonyl group.[15] In organocatalysis by peptides,
and carboxylic acid groups of 6-APA, we performed the the spatial arrangement of the amine and the carboxylic
reaction with Penicillin G (PenG) and 6-APA benzyl ester acid groups has been examined and it was demonstrated
(6-APA-OBn; Table 5, entries 1 and 3). PenG and 6-APA- that even in this case it was quite critical for an efficient
OBn are less effective than 6-APA in terms of reaction catalysis.[16] The bicyclic core of 6-APA is a rigid and bent
yield, but, surprisingly, the best result in terms of enantio- structure with the amino and carboxylic acid functions
selectivity was obtained with Penicillin G (entry 1, eeanti
=
pointing in opposite directions with respect to the azetidi-
80%), in the absence of the primary amino group, whereas none plane, and hence an intramolecular cooperation of the
with the 6-APA O-benzyl ester, the ee was low and, notably, two functional groups in catalysis should be highly limited
with a reversed enantioselectivity in the case of the anti iso- by their geometrical arrangement.
Table 5. Aldol condensation between cyclohexanone and p-nitrobenzaldehyde with different catalysts and catalyst activation mode.[a]
Entry Catalyst [10 mol-%] Additive [mol-%]
t [h]
% Yield
1a + 1b
syn/anti
% eesyn
% eeanti
2
1
2
3
4
5
6
7
8
9
PenG
–
–
–
214
310
238
134
185
112
142
145
195
195
21
3
54
87
83
20
64
90
traces
15
–
–
1
–
4
1
8
2
–
–
50:50
75:35
52:48
27:73
64:36
55:45
64:36
56:44
–
27
Nd[b]
16
47
14
5
10
9
–
80
Nd[b]
–9
32
27
52
20
–14
–
–
PenG (K+ salt)
6-APA-OBn
6-APA
6-APA
PenG
PhCOOH 5%
CF3COOH 5%
CF3COOH 10%
CF3COOH 10%
CF3COOH 10%
PhCOOH 5%
CF3COOH 5%
6-APA
6-APA-OBn
–
10
–
Ͼ99:1
–
[a] Experimental conditions: aldehyde (0.5 mmol), cyclohexanone (2.5 mmol), T = 27 °C. [b] Nd = not detectable.
3158 Eur. J. Org. Chem. 2009, 3155–3160
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

6-APA as Organocatalyst for a Direct Cross-Aldol Reaction
(1.5 mmol) under constant stirring. After the time indicated in
Tables 1–5, the reaction mixture was diluted with water and ex-
tracted with dichloromethane (3ϫ20 mL). The combined organic
phases were dried with anhydrous sodium sulfate and after removal
of the solvent the crude was analysed to determine the yields and
diastereomeric ratios. The residue was purified by flash chromatog-
raphy on silica gel (cyclohexane/ethyl acetate, 85:15) to give a mix-
ture of two aldols, which was analysed by chiral HPLC to deter-
mine the enantiomeric ratios.
The experimental results obtained with 6-APA at dif-
ferent pH values, and with the 6-APA benzyl ester and
PenG, suggest the possibility of there existing two compet-
ing mechanisms: one an imine–enamine mechanism (6-APA
or 6-APA-OBn) and the other a Brønsted acid catalysis (6-
APA or PenG). With PenG and 6-APA-OBn the two
mechanisms act separately, whereas with 6-APA they oper-
ate simultaneously. Brønsted acid catalysis appeared to be
less effective in terms of yield, but gave quite a good
enantioselectivity with respect to the anti isomer (Table 5
entry 1), whereas the imine–enamine catalysis mode was
more effective, but had a low enantioselectivity with an op-
posite stereoinduction in the case of the anti isomer
(Table 5, entry 3). The competition between the two mecha-
nisms in 6-APA catalysis provides a rationale for the limits
we found in the asymmetric catalysis.
When the reactions were conducted in “neat” conditions, the cho-
sen amount of catalyst, aldehyde (0.5 mmol) and freshly distilled
cyclohexanone (2.5 mmol) were mixed. After the times indicated in
Tables 1–5 the reactions were worked up as described above.
Aldols 1a,b, 3–7a,b and enone 2[17] are known products[18,19] and
their NMR spectra agreed with reported data.
The syn/anti ratios were generally determined by HPLC. In the
cases of products 5a,b and 6a,b, the diastereomeric ratios were de-
termined by 1H NMR analysis of the crude product. Enantiomeric
excesses were obtained by HPLC on chiral columns and peak as-
signment was carried out by comparison with reported literature
data.[15]
Conclusions
6-Aminopenicillanic acid (6-APA) has been evaluated for
the first time as a catalyst for a direct cross-aldol reaction.
1a,b: Reversed phase HPLC: tR = 12.90 (1b, anti), 13.10 (1a, syn),
The best results were obtained in neat conditions in which 14.91 (2), 16.40 and 16.56 min (A and AЈ). Chiral HLPC condi-
tions: column AD, hexane/iPrOH (90:10), flow 0.8 mL/min, λ =
210 nm: tR = 21.50 (1a, syn minor isomer), 26.79 (1a, syn major
isomer), 29.29 (1b, anti major isomer, 2S,1ЈR), 39.00 min (1b, anti
minor isomer, 2R,1ЈS).
6-APA proved to be an effective catalyst in terms of yield.
The competition between two different catalysis mecha-
nisms, one an imine–enamine mechanism and the other a
Brønsted acid catalysis, limited the performance with re-
spect to the diastereo- and enantioselectivity. Work is in
progress to design and synthesize more efficient 6-APA de-
rivatives as organocatalysts.
3a,b: Reversed phase HPLC: tR = 12.87 (3b, anti), 13.08 (3a, syn),
15.10 (enone), 16.25 and 16.39 min (hemiacetals). Chiral HLPC
conditions: column AD, hexane/iPrOH (from 99:1 to 90:10 in
20 min), flow 1.0 mL/min, λ = 214 nm: tR = 22.90 (3a, syn minor
isomer), 26.21 (3a, syn major isomer), 28.40 (3b, anti major iso-
mer), 33.30 min (3b, anti minor isomer).
Experimental Section
4a,b: Reversed phase HPLC (from 10% to 80% of CH3CN in
25 min): tR = 22.34 (4b, anti), 22.50 min (4a, syn). Chiral HLPC
conditions: column AD, hexane/iPrOH (from 99:1 to 90:10 in
20 min), flow 1.0 mL/min, λ = 214 nm: tR = 13.80 (4a, syn minor
isomer), 16.60 (4a, syn major isomer), 19.10 (4b, anti major iso-
mer), 21.50 min (4b, anti minor isomer).
General: Solvents were of HPLC grade and were purchased from
commercial suppliers. TLC: Merck 60 F254. Column chromatog-
raphy: Merck silica gel 20–300 mesh. 1H and 13C NMR spectra
were obtained with Varian GEMINI 200 and INOVA 300 spec-
trometers with a 5 mm probe. All chemical shifts have been quoted
relative to deuteriated solvent signals with δ in parts per million
and J in hertz. HPLC–MS: Agilent Technology HP1100, column
ZOBRAX-Eclipse XDB-C8 Agilent Technologies coupled with a
Agilent Technologies MSD1100 single-quadrupole mass spectrom-
eter, full-scan mode from m/z = 50–2600, scan time 0.1 s, ESI spray
voltage 4500 V in positive ion mode (3000 V in negative ion mode),
nitrogen gas 35 psi, drying gas flow 11.5 mL/min, fragmentor volt-
age 20 V. HPLC: Agilent Technology HP1100, column ZOBRAX-
Eclipse XDB-C8 Agilent Technologies. The compounds were
eluted with CH3CN/H2O, gradient from 10–100% of CH3CN in
15 min, then 100% of CH3CN for 10 min. Chiral HPLC: Hewlett–
Packard HP1090 Series II, columns Daicel’s Chiralpack
(25 cmϫ0.46 cm Ø) AD, OD and OJ. The compounds were eluted
with hexane/iPrOH. To set and maintain the temperature in the
range of Ϯ1 °C, a Techne TE-10D Tempunit and Fison Haake K15
were used.
5a,b: Reversed phase HPLC: tR = 13.55 min (5a + 5b). Chiral
HLPC conditions: column OD, hexane/iPrOH (98:2), flow 0.7 mL/
min, λ = 210 nm: tR = 21.26 (5a, syn major isomer), 24.67 (5a, syn
minor isomer), 30.15 (5b, anti minor isomer), 47.21 min (5b, anti
major isomer).
6a,b: Reversed phase HPLC: tR = 13.30 min (5a + 5b). Chiral
HLPC conditions: column AD, hexane/iPrOH (92:8), flow 1.0 mL/
min, λ = 210 nm: tR = 30.50 (6a, syn minor isomer), 37.06 (6a, syn
major isomer), 57.72 (6b, anti major isomer), 64.19 min (6b, anti
minor isomer).
7a,b: Reversed phase HPLC: tR = 15.42 (7b, anti), 15.13 min (7a,
syn). Chiral HLPC conditions: column OJ, hexane/iPrOH (99:1),
flow 1.0 mL/min, λ = 214 nm: tR = 8.45 (7b, anti major isomer),
10.25 (7b, anti minor isomer), 18.11 (7a, syn minor isomer),
19.37 min (7a, syn major isomer).
General Procedure for the Organocatalysed Aldol Reaction: In a
typical experiment, the solvent (2 mL) was placed in a 20 mL test-
tube equipped with a screw cap and magnetic bar. The desired tem-
perature was reached and kept constant by use of a temperature
control apparatus. Catalyst (0.15 mmol) and aldehyde (0.5 mmol)
were added to the test-tube with freshly distilled cyclohexanone
Acknowledgments
Financial support from Ministero dell’Istruzione, dell’Università e
della Ricerca (MIUR) and the University of Bologna (Funds for
Eur. J. Org. Chem. 2009, 3155–3160
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3159

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Received: February 20, 2009
Published Online: May 4, 2009
3160
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Eur. J. Org. Chem. 2009, 3155–3160