Asymmetric aldol reaction catalyzed by a heterogenized proline on a mesoporous support. The role of the nature of solvents

Article abstract of DOI:10.1021/jo070992s

(Chemical Equation Presented) A heterogenized (S)-proline on mesoporous support MCM-41 catalyzes the asymmetric aldol reaction in a wide range of solvents. The progress of the reaction is dependent on the nature of the solvent. Reactions proceed more effi

Full text of DOI:10.1021/jo070992s

Asymmetric Aldol Reaction Catalyzed by a
Heterogenized Proline on a Mesoporous Support.
The Role of the Nature of Solvents
Elisa G. Doyagu¨ez, Fe´lix Caldero´n, Fe´lix Sa´nchez, and
Alfonso Ferna´ndez-Mayoralas*,†
FIGURE 1. Proline derivative grafted into mesoporous MCM-41.
Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la
CierVa 3, 28006 Madrid, Spain
TABLE 1. Solvent Screen for the Aldol Reaction between
p-Nitrobenzaldehyde 1 and Dioxanone 2 in the Presence of
MCM41-Pro
time
(h)
conv.b
(%)
eeb
(%)
mayoralas@iqog.csic.es
entry
solvent (log P)a
anti:synb
1
2
3
4
5
6
7
8
9
formamide (-1.65)
formamide (-1.65)c
DMF (-1.00)
13
13
61
48
61
96
96
96
96
96
96
93
80
82
46
20
23
<5
20
14
2:1
2:1
5:1
2:1
3:1
2:1
2:1
n.d.
2:1
2:1
67
65
82
63
76
63
50
n.d.
65
64
ReceiVed May 14, 2007
DMF (-1.00)d
MeOH (-0.76)
MeCN (-0.33)
THF (0.49)
t-BuOMe (0.94)
CH2Cl2 (1.25)
Toluene (2.50)
10
a Log P is the partition coefficient of the solvent in octanol/water.
b Determined by HPLC analysis. n.d. ) not determined. c Recycled
MCM41-Pro was used as catalyst. d (S)-Proline was used as catalyst in
homogeneous media.
A heterogenized (S)-proline on mesoporous support MCM-
41 catalyzes the asymmetric aldol reaction in a wide range
of solvents. The progress of the reaction is dependent on
the nature of the solvent. Reactions proceed more efficiently
in hydrophilic polar solvents; however, the addition of a small
amount of water has a positive effect on the rate and the
stereoselectivity of the reaction performed in hydrophobic
toluene. The reaction under heterogeneous conditions has
also been performed on chiral aldehydes, furnishing useful
intermediates for the synthesis of azasugars.
main advantages of proline-catalyzed reactions are that this
amino acid is innocuous and nonexpensive and both enantiomers
are available. In addition, the reaction can be performed in a
stereoselective manner, under mild conditions, and without the
need of any metal. However, due to the solubility of proline
the reactions are normally carried out in polar solvents, such as
DMSO or DMF. In this context, we have recently described4
that a proline derivative heterogenized on amorphous silica and
structured mesoporous material MCM-41 (MCM41-Pro, Figure
1) can catalyze the aldol reaction between different aldehydes
and hydroxyacetone. MCM-41 was the most convenient support
to be functionalized since its high surface area allows us to bind
more moles of catalysts per surface unit, consequently decreas-
ing the risk of nonlinear effect usually found in other hetero-
geneous catalysis.5 We also showed that reactions in the
presence of MCM41-Pro can be performed in DMSO and in
hydrophobic toluene, giving aldol products with stereoselec-
tivities in some cases complementary to those obtained by
homogeneous catalysis. Due to the potential effect that the
solvent may have on the progress of the aldol addition, we were
interested in evaluating the role of the solvent for this reaction.
Herein we present the results of the reaction of p-nitroben-
zaldehyde (1) with 2,2-dimethyl-1,3-dioxan-5-one (2) that we
have selected as a standard model, in the presence of MCM41-
Pro (Scheme 1). The influence of the solvent, the presence of
water in the reaction medium, and the change of the linker
moiety used for the attachment of proline to the support have
been evaluated. In addition, the reactions were performed on
chiral aldehydes that furnished useful intermediates for the
synthesis of azasugars. The present work offers new insights
There is a growing interest in asymmetric organocatalysis,1
particularly in the use of the amino acid proline2 and its
derivatives3 as catalysts for asymmetric aldol additions. The
† Fax: (+34)-91-564-4853.
(1) (a) List, B. Chem. Commun. 2006, 819-824. (b) Seayad, J.; List, B.
Org. Biomol. Chem. 2005, 3, 719-724. (c) Berkessel, A.; Gro¨ger, H.
Asymmetric Organocatalysis; VCH: Weinheim, 2004. (d) List, B. AdV.
Synth. Catal. 2004, 9-10, 1021. (e) Houk, K. N.; List, B. Acc. Chem. Res.
2004, 37, 487. (f) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138-5175. (g) List, B. Synlett 2001, 11, 1675-1686.
(2) (a) Enders, D.; Gasperi, T. Chem. Comm. 2007, 88-90. (b) Enders,
D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44, 1210-1212. (c) Northrup,
A. B.; MacMillan, D. W. C. Science 2004, 1752-1755. (d) Northrup, A.
B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int.
Ed. 2004, 43, 2152-2154. (e) Notz, W.; Tanaka, F.; Barbas, C. F., III.
Acc. Chem. Res. 2004, 37, 580-591. (f) Pidathala, C.; Hoang, L.; Vignola,
N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785-2788. (g) Bøevig, A.;
Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun. 2002, 620-621.
(h) Gro¨ger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529-532. (i)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001,
123, 5260-5267. (j) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-
7387. (k) List, B.; Lerner, R.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395-2396.
(3) (a) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876-
7880. (b) Mitchell, C.; Lobb, A.; Ley, S. V. Synlett 2005, 611-614. (c)
Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570-579. (d) Berkessel,
A.; Koch, B.; Lex, J. AdV. Synth. Catal. 2004, 346, 1141-1146. (e) Hartikka,
A.; Arvidsson, P. Tetrahedron: Asymmetry 2004, 15, 1831-1834. (f) Pihko,
P. Angew. Chem., Int. Ed. 2004, 43, 2062-2064f. (g) Mase, N.; Tanaka,
F.; Barbas, C. F., III Angew. Chem. Int. Ed. 2004, 43, 2420-2423. (h)
Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, Ai-Q.; Jiang, Y.-
Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262-5263.
(4) Caldero´n, F.; Ferna´ndez, R.; Sa´nchez, F.; Ferna´ndez-Mayoralas, A.
AdV. Synth. Catal. 2005, 347, 1395-1403.
(5) Corma, A. Chem. ReV. 1997, 97, 2373-2420.
10.1021/jo070992s CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/24/2007
J. Org. Chem. 2007, 72, 9353-9356
9353

TABLE 2. Effect of Water on MCM41-Pro-Catalyzed Aldol
Reactions of 1 and 2
SCHEME 1
H2O
(equiv)
conv.a
(%)
eea
(%)
entry
solvent
anti:syna
1
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
toluene
toluene
toluene
toluene
toluene
0
2
5
10
0
2
5
10
20
20
20
21
22
14
33
47
<5
<5
2:1
3:1
3:1
3:1
2:1
6:1
10:1
n.d.
n.d.
63
73
62
66
64
65
78
n.d.
n.d.
into the effect of the nature of the solvent on proline-catalyzed
reactions under heterogeneous conditions.
The results of the aldol addition between 1 and 2 in the
presence of MCM41-Pro6 at room temperature7 in a variety of
solvents are summarized in Table 1. For comparative purposes
the results using (S)-proline in DMF are also included (entry
4). It could be observed that the catalytic efficiency of MCM41-
Pro decreased as the solvent hydrophobicity increased. Thus,
the aldol reaction proceeded with high conversion in formamide
and DMF (96 and 80%) and with moderate conversion in MeOH
(46%). On the contrary, the reaction in toluene furnished 3 in
low conversion (14%) after 96 h, and in tert-butylmethyl ether
only trace amounts of 3 were observed. In most of the solvents
the diastereoselectivity was low, and the enantioselectivity,
moderate, except for the reaction performed in DMF that led
to the anti isomer with good diastereoselectivity and high ee
value. Moreover, the stereoselectivity obtained in DMF was even
better than that of (S)-proline under homogeneous conditions
(entry 3 versus entry 4). After filtering and washing,8 the catalyst
could be reused in a new reaction that proceeded without
significant differences regarding conversion and stereoselectivity
(entry 2).
On the other hand, it has been reported that small amounts
of water are sometimes beneficial in proline-catalyzed aldol
reactions.9 Considering the proposed mechanism, which is
consistent with an enamine intermediate and the consequent
formation of a molecule of water,10 once the acceptor aldehyde
reacts with the enamine a new C-C bond is formed, and the
resulting iminium intermediate is attacked by a molecule of
water to regenerate the catalyst. Under our heterogeneous
reaction conditions, the water present in the reaction medium
will partition between the organic solvent and the solid surface;
the partition ratio will depend on the hydrophobicity of the
solvent used. In the most hydrophobic solvent, the molecules
of water will tend to remain attached to silanols on the support
and, therefore, the loss of H2O will inhibit proline turnover.
This situation would account for the poor catalytic efficiency
observed when the reactions were carried out in hydrophobic
solvents. On the basis of this assumption,11 we next examined
a Determined by HPLC.
TABLE 3. Aldol Reaction between 1 and 2 in the Presence of
MCM41-Pro(C)
time
(h)
conv.a
(%)
eea
(%)
solvent
anti:syna
formamide
DMF
48
84
84
88
67
79
2:1
2:1
3:1
46
40
34
tolueneb
a Determined by HPLC. b Reaction performed with 5 equiv of water.
TABLE 4. Aldol Reaction between 7 and 8 with 2 in the Presence
of MCM41-Pro and MCM41-Pro(C)
yielda
(%)
entry aldehyde
catalyst
solvent
anti:synb
1
2
3
4
5
6
7
8
7
7
7
7
8
8
8
8
MCM41-Pro
MCM41-Pro
formamide
toluenec
62
30
56
64
52
10
57
44
5:1
3:1
2:1
3:1
3:1
n.d.
3:1
2:1
MCM41-Pro(C) formamide
MCM41-Pro(C) toluenec
MCM41-Pro
MCM41-Pro
formamide
toluenec
MCM41-Pro(C) formamide
MCM41-Pro(C) toluenec
a Isolated yield. b Determined by 1H NMR. n.d. ) not determined.
c Reaction performed with 5 equiv of water.
the effect of addition of water to the reaction of 1 with 2 in two
solvents of distinct hydrophobicity, MeCN and toluene, whose
reactions furnished aldol products in low yields (Table 2). While
in hydrophilic MeCN the addition of small amounts of water
did not affect the production of the aldols (entries 1-4), in
hydrophobic toluene there was an appreciable increase in
conversion when 2 and 5 equiv of water were added.
Interestingly, the reactions in toluene exhibited a progressive
increase of stereoselectivity as water was added up to 5 equiv
(entries 5-7), reaching a diastereoselectivity ratio of 10:1.
However, when 10 and 20 equiv of water were added to toluene,
the yield dropped drastically and only traces of aldol products
were observed (entries 8 and 9). This result could be rationalized
assuming that the added water molecules (up to 5 equiv) gather
together around the interphase solid solution, very close to the
catalytic site, favoring the catalytic cycle. However, with an
excess of water (10 and 20 equiv), the formation of a biphasic
system could be responsible for the drastic drop of reactivity.
The nature of the linker moiety used for attachment of proline
to MCM-41 could also influence the progress of the reactions.
It could be the case that the urea moiety in MCM41-Pro interacts
with the carbonyl group of the substrates in a solvent-dependent
manner, thus affecting the reaction rate and yield. Considering
this possibility, we synthesized a new catalyst MCM41-Pro(C)
in which the urea group was replaced by a carbamate group
(6) The loading (0.7 mmol/g) of the MCM41-Pro catalyst was calculated
by elemental analysis based on nitrogen. Anal. Found: C, 13.87; H, 2.53;
N, 2.95 %.
(7) No reaction was observed when the aldol addition was carried out at
4 °C in two distinct solvents, DMF and toluene, during 72 h.
(8) The catalyst was filtered and thoroughly washed with methanol, ethyl
acetate, dichloromethane, hexane, and diethyl ether (two times each).
(9) (a) Ibrahem, I.; Zou, W.; Xu, Y.; Co´rdova, A. AdV. Synth. Catal.
2006, 348, 211-222. (b) Ward, D. E.; Jheengut, V. Tetrahedron Lett. 2004,
45, 8347-8350. (c) b) Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett 2004,
1891-1896. (e) Tanaka, F.; Thayumanavan, R.; Mase, N.; Barbas, C. F.,
III. Tetrahedron Lett. 2004, 45, 325-3287.
(10) (a) Allemann, C.; Gordillo, R.; Clemente, F.; Ha-Yeon Cheong, P.;
Houk, K. N. Acc. Chem. Res. 2004, 37, 558-569. (b) Clemente, F. R.;
Houk, K. N. Angew. Chem., Int. Ed. 2004, 43, 5766-5768.
(11) The possibility that the support surface can also participate in the
reaction mechanism, in a solvent-dependent manner, cannot be excluded;
for instance, see: Corma, A.; Iborra, S.; Rodr´ıguez, I.; Sa´nchez, F. J. Catal.
2002, 211, 208-215.
9354 J. Org. Chem., Vol. 72, No. 24, 2007

SCHEME 2. Synthesis of MCM41-Pro(C)
SCHEME 3
(Scheme 2). The synthesis of MCM41-Pro(C) was achieved in
a few steps from protected hydroxy-(S)-proline as described in
Scheme 2.
dioxanone 2 with two chiral aldehydes 7 and 8 derived from
tartaric acid (Scheme 2). The results of the reaction of 2 with
7 and 8 in the presence of MCM41-Pro and MCM41-Pro(C) in
formamide and toluene with 5 equiv of water are shown in Table
4. With MCM41-Pro the reactions in formamide furnished 9
and 10 in 62 and 52% yield, respectively, while in toluene a
significant decrease in yield was obtained (30 and 10%,
respectively). However, the catalyst MCM41-Pro(C) bearing a
carbamate moiety furnished 9 and 10 in comparable yields in
both solvents. Concerning stereoselectivity, the reactions fur-
nished exclusively the S-configured carbon at position C-3, with
(4R,3S)/(4S,3S) ratios varying from 2:1 to 5:1. The major aldol
products anti-9 and anti-10 were transformed into six- and five-
membered iminocyclitols by hydrogenation (compounds 11 and
12, Scheme 3).
In summary, we have shown that a heterogeneized (S)-proline
on mesoporous support MCM-41 can catalyze the asymmetric
aldol reaction in solvents of different polarity. This fact leads
to enlarge the application of a fundamental variable, the solvent,
to the study of proline-catalyzed reactions. Under heterogeneous
conditions we have obtained precursors of azasugars from an
aldol addition performed in toluene, a solvent where the use of
(S)-proline is hampered by insolubility problems.
The new catalyst was tested for the reaction of 1 and 2 in
toluene with 5 equiv of water, as well as in formamide and
DMF (Table 3). With this catalyst the reaction in toluene
proceeded more efficiently, giving the aldol products in a
conversion comparable to that obtained in formamide. In the
three solvents, however, the diastereoselectivities and the ee
values were lower than those obtained with MCM41-Pro, which
could be attributed to the configuration change at C-4 of the
proline ring.
We are interested in efficient preparation of iminocyclitols,12
also called azasugars as the ring oxygen of a carbohydrate is
replaced by nitrogen, due to their ability to act as potent
inhibitors of enzymes involved in carbohydrate processing, such
as glycosidases and glycosyltransferases.13 We have recently
reported14 a new route to synthesize compounds of this family
through a proline-catalyzed aldol reaction on aldehydes derived
from diethyltartrate. The main point of this synthetic approach
relies on the possibility of obtaining a variety of azasugars
combining the use of both enantiomers of diethyltartrate as
starting material and (R)- or (S)-proline as catalyst. In connection
with this work we have now evaluated MCM41-Pro and
MCM41-Pro(C) for their ability to catalyze the reaction of
Experimental Section
General Procedure for the Catalytic Asymmetric Aldol
Reaction of p-Nitrobenzaldehyde (1) and Ketone 2 Using
MCM41-Pro. To a suspension of ketone 2 (16.9 mg, 0.13 mmol)
and MCM41-Pro (30% mol; 27.8 mg, loading: 0.7 mmol/g) in the
corresponding solvent (0.21 mL), aldehyde 1 was added (10 mg,
0.065 mmol). The mixture was stirred at rt for the time indicated
in Table 1. Then, the catalyst was separated by centrifugation, and
the filtrate was quenched with saturated aqueous ammonium
chloride solution and extracted with ethyl acetate (3 × 1 mL). The
(12) (a) Bastida, A.; Ferna´ndez-Mayoralas, A.; Go´mez, R.; Iradier, F.;
Carretero, J. C.; Garc´ıa-Junceda, E. Chem.sEur. J. 2001, 7, 2390-2397.
(b) Carpintero, M.; Bastida, A.; Garc´ıa-Junceda, E.; Jime´nez-Barbero, J.;
Ferna´ndez-Mayoralas, A. Eur. J. Org. Chem. 2001, 4127-4135. (c)
Caldero´n, F.; Carpintero, M.; Garc´ıa-Junceda, E.; Ferna´ndez-Mayoralas,
A.; Bastida, A. Lett. Org. Chem. 2005, 2, 247-254.
(13) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beyond; Wiley-VCH: Weinheim, Germany, 1999.
(14) Caldero´n, F.; Doyagu¨ez, E. G.; Ferna´ndez-Mayoralas, A. J. Org.
Chem. 2006, 71, 6258-6261.
J. Org. Chem, Vol. 72, No. 24, 2007 9355

combined organic layers were concentrated under vacuum. Yields
and diastereoselectivities are reported in Table 1.
Acknowledgment. Financial support by the Spanish Gov-
ernment is gratefully acknowledged (Projects CTQ2004-03523/
BQU and MAT2006-14274-C02-01 and -02). F.C. and E.G.D.
thank Ministerio de Educacio´n y Ciencia and CSIC for
predoctoral fellowships (BQU2001-1503 and I3P-BPD2005,
respectively).
General Procedure for the Catalytic Asymmetric Aldol
Reaction of 7 and Ketone 2 Using MCM41-Pro or MCM41-
Pro(C). To a solution of 7 (0.5 mmol) in the solvent (1.6 mL),
ketone 2 (260 mg, 2 mmol) and the catalyst (30% mol; 214 mg for
MCM41-Pro and 163 mg for MCM41-Pro(C)) were added. The
mixture was stirred at rt for 24-72 h. Then, the catalyst was
separated by centrifugation, and the filtrate was quenched with
saturated aqueous ammonium chloride solution and extracted with
ethyl acetate (3 × 1 mL). The combined organic layers were
concentrated under vacuum. Yields and diastereoselectivities are
reported in Table 4.
Supporting Information Available: General information,
experimental procedures, copies of the NMR spectra of compounds
5, 6, 8, and 10, and copies of solid 13C NMR and IR of MCM41-
Pro(C). This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070992S
9356 J. Org. Chem., Vol. 72, No. 24, 2007