Diastereo- and enantioselective direct aldol reactions in aqueous medium: A new highly efficient proline-sugar chimeric catalyst

Article abstract of DOI:10.1002/adsc.201100143

A new synthetic catalyst, capable of acting like an enzyme in the accomplishment of direct aldol reactions, is presented. Excellent results, in terms of chemical yields and diastereo-/enantiomeric ratios, are reported for the catalyzed additions of cycloh

Full text of DOI:10.1002/adsc.201100143

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DOI: 10.1002/adsc.201100143
Diastereo- and Enantioselective Direct Aldol Reactions in
Aqueous Medium: A New Highly Efficient Proline-Sugar
Chimeric Catalyst
Silvana Pedatella,a Mauro De Nisco,a,* Domenico Mastroianni,b Daniele Naviglio,a
Ada Nucci,c and Romualdo Caputoa,*
a
Dipartimento di Chimica Organica e Biochimica, Universitꢀ di Napoli Federico II, Via Cintia 4, I-80126 Napoli, Italy
Fax : (+39)-081-674-393; phone: (+39)-081-674-118; e-mail: denisco@unina.it or rocaputo@unina.it
Tecnogen SpA, Localitꢀ la Fagianeria, Piana di Monte Verna, I-81015 Caserta, Italy
Istituto di Scienze degli Alimenti e della Nutrizione, Universitꢀ Cattolica del Sacro Cuore, Via Emilia Parmense 84,
b
c
I-29122 Piacenza, Italy
Received: February 27, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100143.
Abstract: A new synthetic catalyst, capable of
acting like an enzyme in the accomplishment of
direct aldol reactions, is presented. Excellent re-
sults, in terms of chemical yields and diastereo-/
enantiomeric ratios, are reported for the catalyzed
additions of cyclohexanone to variously substituted
benzaldehydes.
alters enantioselectivities by interrupting the hydro-
gen bonds that are crucial for stabilizing the transition
states of the asymmetric catalytic reactions, and this
may be the reason for the poor enantioselectivity[7] of
the proline-catalyzed aldol reactions in water.
Either the use of cosolvents[6] or, vice versa, at-
tempts to enhance the hydrophilic nature of proline
by grafting on it polyhydroxylated auxiliaries,[8] did
not lead to significantly improved results.
Keywords: aldol reaction; asymmetric synthesis;
green chemistry; l-proline catalyst; organocatalysis
Indeed, another non-secondary aspect of the enam-
ine mechanism is that the reactions occurring in the
aldolase antibodies are considered to be accomplished
in a hydrophobic active site,[9] whereas the amino
functionality of lysine and the hydroxy group of tyro-
The ability of simple organic molecules from the sine seem to be also involved in the catalytic cycle.
“chiral pool” to act like an enzyme represents a re- In fact, small organic catalysts bearing hydrophobic
markable synthetic alternative to many established groups were designed with the purpose of matching
asymmetric transformations. Among the various the hydrophobic nature of the active site in antibod-
enantiomerically pure small organic molecules, amino ies. The results, in this case, were quite encouraging
acids and peptides are extremely interesting asymmet- and some examples of such catalysts are available
ric organocatalysts leading to useful levels of enantio- from the current literature.[10]
selectivity in a wide range of transformations.[1]
Under such circumstances we were stimulated to
In particular, the natural amino acid l-proline acts design a new catalyst that, in our opinion, should
as an enzyme mimic of the class I aldolase,[2] catalyz- have overcome the above-mentioned limits of other
ing an important organic asymmetric transformation, reported proline-based catalysts. Therefore, within
the aldol reaction.[3] The proline-catalyzed asymmetric our current interest in the chemistry of carbohy-
aldol addition is well established to proceed via the drates[11] and peptides as organocatalysts,[12] we have
“enamine mechanism” where the proline amino synthesized an unprecedented l-prolinamide 1 that,
group converts the aldol donor to an enamine and the as highlighted in Figure 1, displays three different do-
carboxylic acid group provides a hydrogen bond to mains, namely a hydrophobic one, represented by the
the acceptor.[4]
cumbersome TBDPS protecting group at the anome-
Although the proposed mechanism is based on the ric hydroxy position of b-glucosamine, a hydrophilic
class I aldolase mechanism, proline has not been dem- one, consisting of the sugar moiety with its three free
onstrated to act as an efficient catalyst in aqueous hydroxy groups, and finally the functional domain
medium.[5] On the other hand it is known[6] that water represented by l-proline nucleus.
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Silvana Pedatella et al.
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Table 1. Cyclohexanone/miscellaneous benzaldehydes aldol
additions in brine, 48C, 48 h, catalyzed by 1 (2 mol%).
R
Yield [%][a]
dr (anti:syn)[b]
ee [%][c]
3-chloro
4-chloro
3-cyano
4-cyano
3-fluoro
4-fluoro
2-methoxy
3-methoxy
4-methoxy
3-methyl
4-methyl
2-nitro
99
99
86
>99
98
99
95
>99
96
99
98
96
>99
98
98
96:4
97:3
98:2
97:3
96:4
96:4
88:12
92:8
87:13
95:5
92:8
98:2
97:3
97:3
91:9
96
98
96
96
96
98
83
94
82
94
87
>99
98
96
92
Figure 1. (2S)-Pyrrolidine-2-carboxamide (1).
Simple d-glucosamine has been already demon-
strated[13] to exert a catalytic role on the direct aldol
reaction of ketones and aromatic aldehydes, although
affording moderate yields and poor enantiomeric
excess of the aldol product. Also poor, and even
worse, results were obtained[14] using d-glucosamine-
l-prolinamide as catalyst for the same kind of reac-
3-nitro
tions in water. On the contrary, small proline-based 4-nitro
4-isopropyl
molecules bearing hydrophobic groups were report-
ACHTUNGTRENNUNG
ed[10d] to act as good organocatalysts for aldol reac-
[a]
[b]
[c]
After chromatography.
Determined by H NMR.
Determined by HPLC on chiral column.
1
tions. Therefore, we combined all this information in
the same molecule that, as expected, turned out to be
an excellent organocatalyst to accomplish direct aldol
reaction of cyclohexanone and aromatic aldehydes.
Experimental details of the synthesis of 1, which is
handily prepared from both commercial d-glucos-
ACHTUNGTRENNUNGamine and l-proline, are reported as Supporting In-
formation along with its full spectroscopic characteri-
zation.
Table 2. Aldol additions as in Table 1, catalyzed by 1, carried
out under various reaction conditions.
R
Mol
[%] [8C]
T
Time Yield dr (anti: ee
[%][a] syn)[b] [%][c]
The new catalyst was extensively tested in the
direct aldol addition of cyclohexanone to variously
substituted benzaldehydes, under standardized condi-
tions (2 mol% loading in brine, 48C, 48 h) obtaining
rather impressive results (Table 1).
Some other miscellaneous experiments, carried out
using different catalyst loadings/solvents/tempera-
tures/reaction times, are reported in Table 2.
All the results show unambiguously that 1 is an effi-
cient catalyst working in aqueous medium (see the
poor results of the reactions carried out in THF,
Table 2) at low temperature. It is also noteworthy the
very low catalyst loading (down to 0.1 mol%, Table 2)
that can be utilized, as well as the significant catalyst
recovery (72–89%) and its reuse (see Supporting In-
formation).
4-cyano
4-cyano
4-cyano
4-cyano
4-cyano (in THF)
4-nitro
4-nitro
4-nitro
4-nitro
2
2
25
48 h 99
95:5
99:1
90:10
99:1
82:18
97:3
93:7
96:4
89:11
99:1
90:10
87
98
85
99
62
98
89
98
82
96
70
À16 48 h 99
0.1 25
4 d
92
82
0.1 À16 4 d
2
10
2
4
48 h 57
À16 48 h 94
25 48 h 98
2
À16 48 h 96
0.1 25
4 d
90
84
4-nitro
4-nitro (in THF)
0.1 À16 4 d
2
4
48 h 52
[a]
After chromatography.
Determined by H NMR.
Determined by HPLC on chiral column.
[b]
[c]
1
The compound 1 was also tested in the addition of 82%). No reversed configuration of the aldol product
acetone and 4-nitrobenzaldehyde (Table 3). The reac- was observed.[15] In our opinion the presence of water
tion with acetone was carried out both in the presence increases the activity of the catalyst because the more
and in the absence of water. In the first case we ob- hydrophilic medium enhances the affinity of the hy-
tained the aldol product in acceptable yield (42–54%) drophobic aldehyde to the hydrophobic moiety of the
and low enantioselectivity (66–70%) (entries 1 and 2). catalyst. When water is absent (THF), the aldehyde is
When the reaction was carried out without water (en- well dissolved in the organic solvent and this causes a
tries 4 and 5) the aldol product was obtained in lower lower yield. These results, however, are mostly paral-
yield (10–12%) and better enantioselectivity (72– leling those reported by various authors for the aldol
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Adv. Synth. Catal. 2011, 353, 1443 – 1446

Diastereo- and Enantioselective Direct Aldol Reactions in Aqueous Medium
Table 3. Acetone/4-nitrobenzaldehyde aldol additions, cata-
lyzed by 1 (2 mol%), carried out under various reaction con-
ditions.
Our results show that the synthetic catalyst 1 works
“in the presence of water”[10d,20] without organic sol-
vent, much like an enzyme accomplishing aldol reac-
tions with very high enantioselectivity in most cases.
It can be regarded as a first example of and a lead for
a new family of enzyme-like organocatalysts carrying
different sugars and/or hydrophobic moieties to be in-
À
vestigated for other C C bond forming reactions.
Solvent
T [8C]
Time
Yield [%][a]
ee [%][b]
brine
brine
brine
THF
THF
25
4
À16
25
4
48 h
48 h
4 d
48 h
48 h
42
54
21
10
12
66
70
75
72
82
Experimental Section
General Procedure for Cyclohexanone/Miscellaneous
Benzaldehydes Aldol Reactions Catalyzed by 1
Into an 8-mL Wheaton clear glass, screw-cap vial, solid 1
(7.7 mg, 1.5ꢂ10À2 mmol) suspended in brine (or THF)
(1 mL), cyclohexanone (3.0 mmol), and the aldehyde under
investigation (0.75 mmol) were charged in sequence. The
mixture was vigorously stirred in the stoppered vial at the
chosen temperature/time (cf. Table 1 and Table 2). After
quenching by 20% aqueous NH4Cl (4 mL) and extraction
with Et2O (3ꢂ5 mL), the organic layers were washed with
brine and dried (Na2SO4). The combined water extracts con-
taining salts and most of the recovered catalyst were freeze-
dried and put aside. Evaporation of the solvents under re-
duced pressure gave a crude residue that was adsorbed on a
preparative layer plate eluting twice with hexane:EtOAc
(7:3) to get residual starting aldehyde and anti plus syn cou-
ples. The anti:syn ratio was determined by 500 MHz
1H NMR. The anti ee was determined by HPLC on a chiral
column (Daicel, Chiralpak, IC). The solid coming from the
freeze-dried water extracts was worked up as reported in
the Supporting Information to recover the residual catalyst.
Recovery range: 72–89% (when 2 mol% used). All the ex-
periments were duplicated.
[a]
After chromatography.
Determined by HPLC on chiral column.
[b]
addition of acetone and aromatic aldehydes in the
presence of water.[2e,4d,5,10b,15,16]
The performances of the catalyst 1 can be account-
ed for by considering that in water (even more in
brine, due to the salting-out effect[17]) the catalyst
molecules may undergo molecular aggregation, much
like surfactants, creating a local hydrophobic microen-
vironment in which reactions can take place. In other
words, in the transition state the organic non-polar re-
actants would be buried in the hydrophobic environ-
ment[18] whereas the entire system would be kept in
water by a hydrophilic surface. After accomplishment
of the reaction, the moderately polar aldol molecules
would be squeezed out of the hydrophobic environ-
ment and locate themselves closer to the polar surface
of the catalyst.[19]
As a matter of fact, the only significant variable in
the use of catalyst 1 in aqueous medium seems to be
the temperature: in our opinion this is in line with the
proposed transition state (Figure 2) insofar as low
temperature could reduce the molecular freedom and,
Acknowledgements
The authors thankfully acknowledge the skilful collaboration
of Semiha Bektas¸ (ERASMUS fellow, 2009). 1H and
consequently, contribute to the aggregation that cre- 13C NMR spectra were performed at Centro Interdipartimen-
tale di Metodologie Chimico-Fisiche, Universitꢀ di Napoli
Federico II. The Varian Inova 500 MHz NMR instrument is
the property of Consorzio INCA.
ates a hydrophobic environment to hold the non-
polar reactants.
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