Asymmetric aldol reaction using immobilized proline on mesoporous support

Article abstract of DOI:10.1002/adsc.200505058

The aldol reaction of hydroxyacetone with different aldehydes using immobilized proline on a mesoporous support, assisted by heat and microwaves, has been explored. It was found that heterogenized L-proline on MCM-41 catalyzed aldol reactions in both hydr

Full text of DOI:10.1002/adsc.200505058

FULL PAPERS
Asymmetric Aldol Reaction Using Immobilized Proline on
Mesoporous Support
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Felix Calderon, Raquel Fernandez, Felix Sanchez, Alfonso Fernandez-Mayoralas*
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Instituto de Química Organica General, CSIC, C/Juan de la Cierva 3, 28006, Madrid, Spain
Fax: (þ34)-91-564-4853, e-mail: mayoralas@iqog.csic.es
Received January 27, 2005; Accepted: April 29, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The aldol reaction of hydroxyacetone with plementary to the homogeneous catalyst. The hetero-
different aldehydes using immobilized proline on a geneous catalysts could be reused without significant
mesoporous support, assisted by heat and micro- lost of stereoselectivity.
waves, has been explored. It was found that hetero-
genized l-proline on MCM-41 catalyzed aldol reac- Keywords: aldol reaction; arylmethoxyacetic acids;
tions in both hydrophilic and hydrophobic solvents, mesoporous material; organic catalysis; l-proline;
and provided stereoselectivities in some cases com- supported catalysts
Introduction
The aldol reaction is recognized as being one of the most
powerful and popular methods for the construction of
[1]
À
C C bonds. Organocatalysis, in particular the use of
the amino acid proline[2] and its derivatives,[3] has recent-
ly experienced a renaissance in catalytic asymmetric al-
dol condensations. The main advantages of this method
are that the reaction can be performed in a stereoselec-
tive manner, under mild conditions and without the
need of any metal. In addition, both enantiomers of pro-
line are available. Froma practical point of view, it
would be desirable to have the catalyst immobilized so
Scheme 1. Aldol condensation between hydroxyacetone and
different aldehydes catalyzed by l-proline or mesoporous
that the product purification can be facilitated and the material.
catalyst recycled. One method to immobilize the cata-
lyst is to covalently anchor the proline onto a solid carri-
er. Functionalized pure silica mesoporous materials
Results and Discussion
have been shown to be excellent materials for the prep-
aration of heterogenized catalysts.[4]
Synthesis of the Catalyst
Here we describe our results of a comparative study of
aldol reactions of different aldehydes with hydroxyace-
tone using proline either free or covalently anchored to The synthesis of the heterogenized catalyst was carried
mesoporous MCM-41 (Scheme 1). We were interested out following the route described in Scheme 2.
in this reaction since it furnishes 1,2-diols which may
Several mesoporous and lamellar siliceous materials
be used in the synthesis of carbohydrate analogues as in- with different topologies were used to heterogenize pro-
hibitors of glycosidases and glycosyltransferases.[5]
line derivatives 11a and 11b. The results (summarized in
Table 1) indicated that functionalized MCM-41 with l-
proline (MCM41-Pro) gave the best results. Interesting-
ly, the heterogenized catalyst could be reused for a sec-
ond and third run without significant lost of stereoselec-
tivity, but with a slight reduction of the yield, probably
due to a loss of catalytic material.
Adv. Synth. Catal. 2005, 347, 1395–1403
DOI: 10.1002/adsc.200505058
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Aldol Condensations
Once we had found MCM41-Pro to be the best hetero-
genized catalyst, we next studied condensations with dif-
ferent aldehydes using this catalyst and, for comparative
purpose, l-proline (table 2). While the proline-cata-
lyzed reactions require highly polar solvents (DMSO,
DMF, mixture of DMSO/water), heterogenized catalyst
MCM41-Pro allowed us to use non-polar solvents. The
reactions with l-proline were performed following the
described conditions for aldehydes 1–3[2c] at roomtem-
perature for 24–72 h. In the presence of MCM41-Pro,
mixtures were heated in DMSO or toluene at 908C for
24–72 h. The absolute configurations of the 1,2-diol
1
products have been assigned fromthe H NMR spectra
of their (R)- and (S)-arylmethoxyacetic acid diesters, as
discussed below. l-Proline-catalyzed reactions with al-
dehydes 1–3 gave similar results as reported previous-
ly.[2c] In general, yields were higher using the homogene-
ous conditions, although rather dependent on the type of
aldehyde. Concerning the stereoselectivity, for alde-
hydes 1 and 2 both proline and MCM41-Pro gave the
highest diastereo- and enantioselectivities, the anti-
(1S,2S)-diol being the main product. However, alde-
hydes 3–5 afforded different stereoselectivities depend-
ing on the catalyst. Benzaldehyde 3 in the presence of
proline gave the anti-1,2-diol in a 2.5:1 diastereoselec-
tivity ratio (entry 7), however with MCM41-Pro a mix-
ture was obtained in which the syn-(1S,2R)-diol slightly
predominated (entries 8 and 9). In the case of the l-
threose derivative 4, the diastereoselectivity of the reac-
tion reversed upon changing from l-proline (d.r., 2.8:1)
to MCM41-Pro/toluene (d.r., 1:2.8). For the azido alde-
hyde 5, the l-proline-catalyzed reaction gave the anti-
diol with good yield and stereoselectivity, while the het-
erogenized catalyst afforded poor results. Therefore,
these results indicate that the immobilization of proline
on a mesoporous silica support gives a heterogenized
catalyst for aldol reactions that works in hydrophobic
solvents and provides stereoselectivities in some cases
complementary to those of the homogeneous catalyst.
In order to know if the stereoselectivity changes ob-
served with MCM41-Pro could be ascribed to the pres-
ence of the substituent at C-4 of the proline ring, we pre-
pared a model compound having a referable t-butoxy-
carbamate group at this position (13, Scheme 3). Con-
densations of aldehydes 1–4 with hydroxyacetone in
the presence of 13 under the conditions applied to
MCM41-Pro gave stereoselectivities similar to those ob-
tained with l-proline (Table 3).
Scheme 2. Reagents and conditions: a) (i) Et3N, ClCOOEt,
THF, 08C, 30 min; (ii) BnOH, reflux, 24 h, 70% for 6a; t-
BuNH2, reflux, 2 h, 89.5% for 6b; b) TsCl, Py, r.t., 48 h,
80% for 7a; 100% for 7b; c) NaN3, DMF:water, 708C, 48 h,
80% for 8a;100% for 8b; d) Pd/C (5%), AcOEt, 20 h, 89%
for 9a; 97% for 9b; e) (EtO)3Si(CH2)3NCO, CH2Cl2, r.t.,
18 h, 100%; f) Pd/C, cyclohexene, EtOH, r.t., 15 min for
11a;1 h for 11b, 100%; g) toluene, reflux, 18 h.
Table 1. Asymmetric aldol reactions between 1 and 3 with
hydroxyacetone catalyzed by different heterogenized cata-
lysts.
Aldehyde
Catalyst[c]
Yield [%]
d.r.[d]
1[a]
MCM41-Pro (0.47)
MCM41-Pro (0.47)
MCM41-Pro (0.47)
ITQ2-Pro (0.64)
45
42
40
40
13
30
20
55
55
50
40
20
27
20
>20: 1
>20: 1
>20: 1
>20: 1
>20: 1
>20: 1
>20: 1
1: 1.4
1: 1.4
1: 1.3
1: 1.3
1: 1
1[a, e]
1[a, f]
1[a]
1[a]
ITQ6-Pro (0.33)
1[a]
Silica-Pro(OH) (0.52)
Silica-Pro(NH) (0.43)
MCM41-Pro (0.47)
MCM41-Pro (0.47)
MCM41-Pro (0.47)
ITQ2-Pro (0.64)
ITQ6-Pro (0.33)
Silica-Pro(OH) (0.52)
Silica-Pro(NH) (0.43)
1[a]
3[b]
3[b, e]
3[b, f]
3[b]
3[b]
3[b]
1: 1
1: 1.3
3[b]
Therefore, the stereoselectivity changesobtained with
MCM41-Pro as compared to l-proline must be related
to interactions of the reactants with the solid support.
One possibility for the case of aldehydes 4 and 5, which
gave the most important changes of stereoselectivity,
could be the development of hydrogen bonding-type in-
teractions between the silanols on the support and some
[a]
Roomtemperature, 24 h, DMSO.
908C, 24 h, DMSO.
The catalyst loading (mmol/g) is shown in parenthesis.
d.r.¼anti/syn. The ratio was determined by GC.
The catalyst was reused for a second run.
[b]
[c]
[d]
[e]
[f]
The catalyst was reused for a third run.
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Asymmetric Aldol Reaction Using Immobilized Proline
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Table 2. Asymmetric aldol reactions catalyzed by l-proline and MCM41-Pro.
Entry
Aldehyde
Catalyst[a]
Solvent
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
1
1
1
2
2
2
3
3
3
4
4
4
5
5
5
A
B
B
A
B
B
A
B
B
A
B
B
A
B
B
DMSO
DMSO
Toluene
DMSO
DMSO
Toluene
DMSO
DMSO
Toluene
DMSO
DMSO
Toluene
DMSO
DMSO
Toluene
75
55
55
55
60
55
80
55
60
70
72
60
75
30
15
>20: 1
>20: 1
>20: 1
>20: 1
>20: 1
>20: 1
>99
>99
>99
80
70
70
80
70
70
–
2.5: 1
1: 1.4
1: 1.6
2.8: 1
1: 1.6
1: 2.8
6: 1
9
10
11
12
13
14
15
–
–
–
–
1: 1.4
1: 1.6
–
[a]
A¼l-proline; B¼MCM41-Pro (0.52 mmol/g).
[b]
[c]
[d]
Yield calculated on isolated product.
1
d.r.¼anti/syn. The ratio was determined by H NMR or GC.
1
The ee values were determined by chiral-phase GC or by H NMR after double derivatization (see text). All values are
referred to the major diastereomer.
the silanol groups of the support surface could interact
with the carbonyl group of the aldehyde resulting in po-
larization of the group and, eventually, increasing the re-
action rate.[6] This effect would account for the higher
yields of condensation products obtained with
MCM41-Pro as compared to the model 13. In spite of
the advantages that the heterogenized catalyst could of-
fer, the harsh conditions required for condensations
Scheme 3. Reagents and conditions: a) t-BuNCO, CH2Cl2,
r.t., 1 h, 100%; b) Pd/C, cyclohexene, EtOH, reflux, 15 min,
100%.
(908C and long reaction times) may lead to decomposi-
tion of aldehyde and/or products. Indeed, this is proba-
bly the cause of the lower yield obtained in some cases
Table 3. Asymmetric aldol reaction catalyzed by 13 in
DMSO.
Table 4. Asymmetric aldol reactions catalyzed by l-proline
and MCM41-Pro in DMSO with the assistance of microwave
heating.
Aldehyde
t [h]
Yield [%]
d.r.[a]
ee [%][b]
Aldehyde Catalyst[a]
t
Yield d.r.[b]
[min] [%]
ee
1
2
3
4
48
72
24
24
30
20
20
20
>20: 1
>20: 1
>99
>99
80
[%][c]
2.2: 1
2.8: 1
1
1
2
2
3
3
4
4
5
5
A
B
A
B
A
B
A
B
A
B
10
10
10
10
10
30
10
25
10
15
60
60
90
90
65
70
60
60
65
55
>20: 1
>20: 1
>20: 1
>20: 1
>99
>99
>99
>99
75
80
–
–
–
–
[a]
d.r.¼anti/syn. The ratio was determined by GC.
[b]
The ee values were determined by chiral-phase GC. All
values are referred to the major diastereomer.
2.2: 1
1: 1.4
2.1: 1
1: 1.6
3: 1
oxygen or nitrogen atomof the R substituent in the alde-
hyde, forcing an orientation of the reactant which leads
to the syn-diol product. This interaction would be fa-
vored in non-polar toluene, which would explain the in-
crease of syn-diol formation in the reaction of 4 cata-
lyzed by MCM41-Pro when changing fromDMSO to
toluene (see entries 11 and 12 in Table 1). In addition,
1: 1.3
–
[a]
[b]
A¼l-proline; B¼MCM41-Pro (0.52 mmol/g).
1
d.r.¼anti/syn. The ratio was determined by H NMR or
GC.
[c]
The ee values were determined by chiral phase GC. All va-
lues are referred to the major diastereomer.
Adv. Synth. Catal. 2005, 347, 1395–1403
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Figure 1. Diagnostic DdRS signs for the four possible stereo-
isomers.
with MCM41-Pro compared with proline. In an attempt
to overcome this problem, the reactions were tried un-
der less aggressive conditions by assistance of micro-
waves. Thus, aldehydes 1–5 were reacted with hydrox-
yacetone in the presence of MCM41-Pro under micro-
wave irradiation using a household microwave oven
(900 W). For comparative purposes proline-catalyzed
reactions were also tested under these conditions. The
results are summarized in Table 4. Reaction times
were drastically reduced, providing aldols at roomtem-
perature in only few minutes. Moreover, under these
conditions yields for MCM41-Pro were improved with
most of the aldehydes, being most noticeable in the cases
of 2 (from55 to 90%) and 5 (from30 to 55%).
Figure 2. DdRS values for diester derivatives of aldol products.
Plain and bold numbers correspond to values from MPA and
9-AMA, respectively.
tic acid (MPA) and 9-anthrylmethoxyacetic acid (9-
AMA), are shown.
In the case of the diesters 14 and 15, the absolute con-
figurations determined using the 9-AMAwere in agree-
ment with that reported for the corresponding diol.
Determination of Absolute Configuration
To assign the absolute configuration of the 1,2-diol prod- However, the use of MPA gave smaller DdRS values for
ucts we employed a recentlydescribed method involving the protons bound to the new chiral centers (H-1 and
the formation of the corresponding diesters with (R)- H-2) and the signs for H-1 in diesters 14 and 15 did not
and (S)-arylmethoxyacetic acids (AMAA) and compar- match with the expected configuration. To understand
ison of the DdRS signs of their 1H NMR spectra.[7] Follow- these differences in sign, the structures of MPA diesters
ing this procedure, the diagnostic DdRS signs for the four 14 and 15 were minimized (HTF, 6-31G*, see Supporting
possible stereoisomers of our aldol products are repre- Information) and it was found that the more stable con-
sented in Figure 1. Since the absolute configuration of formation did not correspond with that established by
the main reaction product of aldehydes 1–3 using l-pro- Riguera et al. to have an effective shielding/deshielding
line was reported,[2c] it was used as a probe for testing the effect. Due to the higher accuracy using 9-AMA, the ab-
reliability of this assignment method. In Figure 2 the solute configurations of the aldol products fromalde-
signs of the DdRS experimentally obtained for protons hydes 4 and 5 were determined by analysis of their 9-
considered of diagnostic value of the aldol products, af- AMA diesters 18–21. In this way the anti-diol products
ter derivatization with (R)- and (S)-methoxyphenylace- were characterized as the (1S,2S)-configured diol (die-
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Asymmetric Aldol Reaction Using Immobilized Proline
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ture was stirred at 08C for 1 h. The resulting solid was removed
by filtration and washed with AcOEt. After 1 h at this temper-
ature, the resulting solid was removed by filtration and washed
with AcOEt. The filtrate was concentrated under vacuumand
the residue was dissolved in AcOEt (20 mL) and washed with
water (3ꢀ40 mL), NaHCO3 (3ꢀ40 mL) and NaCl (3ꢀ
40 mL). The organic layer was dried over Na2SO4 and the sol-
vent evaporated. The residue was recystallized from(toluene/
cyclohexane) to afford 6b; yield: 17.2 g (89.5%); mp 97–998C;
ster derivatives 18 and 20), and the syn-product as
(1S,2R)-diol (diester derivatives 19 and 21).
Conclusion
In conclusion, a heterogeneous methodology for direct
asymmetric aldol condensations where the catalyst can
be retrieved and recycled has been developed by heter-
ogenizing proline on the mesoporous material MCM-41.
Condensations of some aldehydes with hydroxyacetone
have resulted in aldol products with moderate to good
yields and stereoselectivities, in some cases leading to
the formation of the syn-diol as main product. With
the assistance of microwave heating, reaction times
were drastically decreased and yields were generally im-
proved. In addition, we have shown that derivatization
of aldol products using 9-AMA, as described previous-
ly,[7] is an appropriate method to assign by NMR the ab-
solute configuration of aldols.
1
[a]2D5: À12.7 (c 1, EtOH). H NMR (300 MHz, CDCl3): d¼
7.42–7.30 (m, 5H, Ph), 5.22–5.15 (m, 2H, CH2Ph), 4.52–4.49
(m, 1H, H-4), 4.32 (m, 1H, H-2), 3.62–3.55 (m, 2H, CH2-5),
2.39–2.19 (m, 2H, CH2-3), 1.2 (s, 9H, t-Bu); 13C NMR
(75 MHz, DMSO, 808C): d¼169.7, 154.5, 136.2, 128.5, 128.3,
128.1, 65.4, 60.0, 59.2, 51.9, 35.2, 28.4; MS (EI): m/z¼321.2
(Mþ1; calcd. for Mþ: 320.1); Anal. calcd. for C17H24N2O4: C
63.7, H 7.5, N 8.7%; found: C 63.9, H 7.5, N 8.6%.
(2S,4R)-1,2-Dibenzyloxycarbonyl-4-(p-
toluenesulfonyloxy)pyrrolidine (7a)
To a cooled solution (08C) of 6a (3.9 g, 10.9 mmol) in dry pyr-
idine ( 10 mL) was added p-toluenesulfonyl chloride (2.58 g,
13.6 mmol). The temperature was allowed to gradually rise
to roomtemperature over 1 h. After 48 h the solvent was
evaporated and the crude reaction product was purified by col-
umn chromatography (hexane/AcOEt, 4:1) to give 7a as a yel-
low oil; yield: 4.46 g (80%); [a]2D5: À25.3 (c 1, EtOH). 1H NMR
(300 MHz, CDCl3): d¼7.83–7.69 (m, 4H, PhTs), 7.4–7.2 (m,
10H, Ph), 5.22–5.0 (m, 5H, 2CH2Ph, H-4), 4.56–4.48 (m, 1H,
H-2), 3.79–3.64 (m, 2H, CH2-5), 2.65–2.50(m, 1H, CHB-
Experimental Section
(2S,4R)-1,2-Dibenzyloxycarbonyl-4-
hydroxypyrrolidine (6a)
Ethyl chloroformate (1.43 mL, 15 mmol) was added dropwise
to a stirred solution of (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-
proline (4 g, 15 mmol) and triethylamine (2.1 mL, 15 mmol)
in anhydrous THF (22 mL) at 08C. After stirring at this tem-
perature for 30 min, benzyl alcohol (2.5 mL, 20 mmol) was
added and the reaction mixture was refluxed for 24 hours.
The resulting solid was removed by filtration and washed
with AcOEt. The filtrate was concentrated under vacuum
and the residue dissolved in AcOEt (20 mL) and washed
with water (3ꢀ40 mL), NaHCO3 (3ꢀ40 mL) and NaCl (3ꢀ
40 mL). The organic layer was dried over Na2SO4 and the sol-
vent was evaporated. The residue was purified by column chro-
matography (hexane/AcOEt, 2:1) to afford 6a as a pale yellow
CHA-3), 2.48 (s, 3H, CH3PhTs), 2.3 (m, 1H, CHB-CHA-3); MS
þ
¼
(EI): m/z 510.3 (Mþ1, calcd. for M : 509.1), 532.3 (Mþ
23); anal. calcd. for C27H27NO7S: C 63.6, H 5.3, N 2.7, S 6.2%;
found: C 63.2, H 5.6, N 2.6, S 6.8%.
(2S,4R)-1-Benzyloxycarbonyl-2-tert-
butylaminocarbonyl-4-(p-
toluenesulfonyloxy)pyrrolidine (7b)
To a cooled solution (08C) of 6b (4 g, 12 mmol) in dry pyridine
(12.1 mL) was added p-toluenesulfonyl chloride (2.86 g,
15 mmol). The temperature was allowed to gradually rise to
roomtemperature over 1 h. After 48 h the solvent was evapo-
rated and the crude reaction product was purified by column
chromatography (hexane/AcOEt, 6:1) to give 7b as a yellow
oil; yield: 3.9 g (70%); [a]2D5: þ600 (c 2, CHCl3). H NMR
1
(300 MHz, CDCl3): d¼7.42–7.18 (m, 10H, Ph), 5.32–4.98
(m, 4H, 2CH2Ph), 4.60–4.48 (m, 2H, H-2, H-4), 3.72–3.45
(m, 2H, CH2-5), 2.4–2.0 (m, 2H, CH2-3); 13C NMR (75 MHz,
DMSO, 808C): d¼173.7, 152.5, 136.2, 135.7, 135.4,
135.0,134.7, 134.4, 128.5, 128.0, 65.6, 60.4, 59.2, 58.9, 52.5,
35.2; MS (EI): m/z¼356.3 (Mþ1; (calcd. for Mþ: 355.1),
378.3 (Mþ23); anal. calcd. for C20H21NO5: C 67.5, H 5.9, N
3.9%; found: C 67.9, H 6.2, N 4.2%.
1
oil; yield: 5.9 g (100%); [a]2D5: À12.7 (c 1, EtOH). H NMR
(300 MHz, CDCl3): d¼7.83–7.22 (m, 9H, Ph), 5.22–5.0 (m,
3H, CH2Ph, H-4), 4.32–4.22 (m, 1H, H-2), 3.92–3.55 (m, 2H,
CH2-5), 2.73–2.10 (m, 2H, CH2-3), 2.48 (s, 3H, CH3PhTs), 1.2
(s, 9H, t-Bu); MS (EI): m/z¼475.2 (Mþ1, calcd. for Mþ:
474.1); anal. calcd. for C24H30N2O6S: C 60.7, H 6.3, N 5.9, S
6.7%; found: C 60.7, H 6.4, N 6.2, S 6.3%.
(2S,4R)-1-Benzyloxycarbonyl-2-tert-
butylaminocarbonyl-4-hydroxypyrrolidine (6b)
Ethyl chloroformate (7.05 g, 65 mmol) was added dropwise to
a stirred solution of (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-
proline (17.21 g, 65 mmol) and triethylamine (6.56 mL,
65 mmol) in anhydrous THF (80 mL) at 08C. After 30 min, t-
butylamine (6.63 g, 91 mmol) was added and the reaction mix-
(2S,4S)-4-Azido-1,2-dibenzyloxycarbonylpyrrolidine
(8a)
Sodiumazide (1.14 g) was dissolved in a mixture of DMF:water
(40:6 mL) and 7a (4.46 g, 8.8 mmol) was added. The mixture
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FULL PAPERS
was heated at 708C for 48 h. After this time solvent was evapo-
rated under reduced pressure and the residue was dissolved in
diethyl ether (20 mL), washed with NaCl saturated(3ꢀ30 mL)
and dried over Na2SO4. After evaporation of the solvent the
residue was chromatographed (hexane/AcOEt, 1:1) to afford
8a as a pale oil; yield: 3.34 g (80%); [a]2D5: À33.5 (c 1, EtOH). 1H
NMR (300 MHz, CDCl3): d¼7.47–7.32 (m, 5H, Ph), 5.30–
4.98 (m, 4H, 2CH2Ph), 4.49–4.32 (m, 1H, H-4), 4.16–3.99 (m,
1H, H-2), 3.74–3.60 (m, 1H, CHB-CHA-5), 3.53–3.39 (m, 1H,
CHB-CHA-5), 2.49–2.30 (m, 1H, CHB-CHA-3), 2.18–2.12 (m,
1H, CHB-CHA-3); 13C NMR (75 MHz, DMSO, 808C): d¼
171.0, 154.2, 136.2, 135.4, 135.4, 135.0,135.4, 134.7, 128.5,
128.0, 67.2, 67.1, 59.2, 58.0 , 52.3, 35.5; MS (EI): m/z¼381.2
(Mþ1, calcd. for Mþ: 380.2), 403.3 (Mþ23); anal. calcd. for
C20H20N4O4: C 63.1, H 5.3, N 15.2%; found: C 63.0, H 5.3, N
15.4%.
(2S,4S)-4-Amino-1-benzyloxycarbonyl-2-tert-
butylaminocarbonylpyrrolidine (9b)
Azide 8b (500 mg, 1.44 mmol) was dissolved in AcOEt (7 mL)
and Pd/C (5%) was added (5 mg). The suspension was then stir-
red under hydrogen for 16 h. After this time, the solution was
filtered through Celiteꢁ and washed with AcOEt. Removal
of the solvent under reduced pressure and purification by col-
umn chromatography (CH2Cl2/MeOH, 20:1) afforded amine
9b as a yellow oil; yield: 450 mg (97%); [a]2D5: À13.7 (c 1,
1
CHCl3). H NMR (300 MHz, CDCl3): d¼7.43–7.22 (m, 5H,
Ph), 5.22–5.10 (m, 2H, CH2Ph), 4.21–4.17 (m, 1H, H-4),
3.73–3.64(m, 2H, H-2), 3.66–3.58 (m, 1H, CHB-CHA-5),
3.32–3.24 (m, 1H, CHB-CHA-5), 2.3–2.22 (m, 1H, CH2-3), 1.3
(s, 9H, t-Bu);13C NMR (75 MHz, DMSO, 808C): d¼171.3,
155.3, 136.3, 128.2, 127.8, 127.7, 67.7, 61.1, 55.7, 50.7, 50.2,
38.2. MS (EI): m/z¼320.2 (Mþ1, (calcd. for Mþ: 319.1);
anal. calcd. for C17H25N3O3: C 63.9, H 7.8, N 13.1%; found: C
64.0, H 7.8, N 13.2%
(2S,4S)-4-Azido-1-benzyloxycarbonyl-2-tert-
butylaminocarbonylpyrrolidine (8b)
(2S,4S)-1,2-Dibenzyloxycarbonyl-4-(3-
triethoxysilylpropylaminocarbonylamino)pyrrolidine
(10a)
To a solution of sodium azide (0.9 g, 14 mmol) in DMF (50 mL)
7b (5 g, 10 mmol) was added. The mixture was heated at 708C
for 48 h. After this time solvent was evaporated under reduced
pressure and the residue was dissolved in diethyl ether
(20 mL), washed with NaCl saturated (3ꢀ30 mL) and dried
over Na2SO4. After evaporation the crude reaction product
was chromatographed (hexane/AcOEt, 1:1) furnishing 8b as
To a solution of 9a (2.20 g, 6.21 mmol) in anhydrous CH2Cl2
(32 mL) was added triethoxysilylpropyl isocyanate (1.53 g,
6.21 mmol). The reaction mixture was stirred under Ar at
roomtemperature for 18 h. Evaporation of the solvent gave
10a which was used without further purification; yield: 3.69 g
(100%); [a]2D5: À16.5 (c 1, CH2Cl2). 1H NMR (300 MHz,
CDCl3): d¼7.29–7.22 (m, 10H, Ph), 5.23–4.87 (m, 4H, 2
CH2Ph), 4.47–4.31 (m, 1H, H-4), 4.09–4.02 (m, 1H, H-2), 3.8
(dt, 6H, CH3CH2OSi), 3.6–3.5 (m, 2H, CH2-5), 3.1 (m, 2H,
CH2NHCONH), 2.4–1.9 (m, 2H, CH2-3), 1.5 (m, 2H, CH2
CH2NHCONH), 1.2 (t, 9H, CH3CH2OSi); 13C NMR
(75 MHz, DMSO, 808C): d¼174.0, 157.3, 136.0, 129.2, 128.1,
127.4, 127.1, 67.0, 58.3, 57.9, 54.2, 49.4, 44.7, 37.2, 23.4, 18.3, 8.
MS (EI): m/z¼624.5 (Mþ23, calcd. for Mþ: 601.2); anal. calcd.
for C30H43N3O8Si: C 59.8, H 7.2, N 6.9%; found: C 59.5, H 7.3, N
7.0%.
1
a pale oil; yield: 3.6 g (100%); [a]2D5: þ11.0 (c 1, EtOH). H
NMR (300 MHz, CDCl3): d¼7.43–7.22 (m, 5H, PhTs), 5.32–
5.0 (m, 2H, CH2Ph), 4.42–4.33 (m, 1H, H-4), 4.2 (t, 1H, CH2-
3), 3.73–3.42 (m, 2H, CH2-5), 2.68–2.2 (m, 2H, CH2-3), 1.3
(s, 9H, t-Bu); 13C NMR (75 MHz, DMSO, 808C): d¼169.7,
155.5, 136.0, 128.5, 128.2, 128.0, 67.6, 60.4, 58.9, 52.5, 34.5,
28.4; MS (EI): m/z¼346 (Mþ1, (calcd. for Mþ: 345.1); anal.
calcd. for C17H23N5O3: C 59.1, H 6.7, N 20.2%; found: C 59.5,
H 6.7, N 20.6%.
(2S,4S)-4-Amino-1,2-dibenzyloxycarbonylpyrrolidine
(9a)
(2S,4S)-1-Benzyloxycarbonyl-2-tert-
butylaminocarbonyl-4-(3-
Azide 8a (2.46 g, 6.36 mmol) was dissolved in AcOEt (21 mL)
and Pd/C (5%) was added (90 mg). The suspension was then
stirred under hydrogen for 20 h. After this time, the solution
was filtered through Celiteꢁ and washed with AcOEt. Remov-
al of the solvent under reduced pressure and purification by
column chromatography (CH2Cl2/MeOH 20:1) afforded
amine 9a as a yellow oil; yield: 2.32 g (89%); [a]2D5: þ8.87 (c
triethoxysilylpropylaminocarbonylamino)pyrrolidine
(10b)
To a solution of 9b (924 mg, 2.89 mmol) in anhydrous CH2Cl2
(15 mL) was added triethoxysilylpropyl isocyanate (716 mg,
2.89 mmol). The reaction mixture was stirred under Ar at
roomtemperature for 18 h. Evaporation of the solvent gave
10b that was used without further purification; yield: 1.635 g
(100%); [a]2D5: À12.4 (c 1, CH2Cl2). 1H NMR (300 MHz,
CDCl3): d¼7.1 (m, 5H, Ph), 5.12–4.87 (m, 2H, CH2Ph),
4.55–4.31 (m, 1H, H-4), 4.12–3.94 (m, 1H, H-2), 3.99–3.72
(dt, 6H, CH3CH2OSi), 3.84–3.33 (m, 2H, CH2-5), 3.27–3.15
(m, 2H, CH2NHCONH), 2.10–1.92 (m, 2H, CH2-3), 1.74–
1.55 (m, 2H, CH2CH2NHCONH), 1.3 (s, 9H, t-Bu), 1.1 (t,
9H, CH3CH2OSi), 0.66 (t, 2H, CH2Si); 13C NMR (75 MHz,
DMSO, 808C): d¼172.0, 157.8, 156.6, 137.0, 128.6, 128.3,
128.2, 67.4, 61.2, 58.5, 55.8, 51.1, 50.2, 43.2, 32.5, 28.7, 28.5,
1
1, CHCl3). H MNR (300 MHz, CDCl3): d¼7.33–7.15 (m,
10H, Ph), 5.20–4.93 (m, 4H, 2CH2Ph), 4.40–4.327 (m, 1H,
H-4), 3.73–3.63 (m, 1H, H-2), 3.52–3.25 (m, 1H, CHB-CHA-
5), 3.30–3.22 (m, 1H, CHB-CHA-5), 2.44–2.34 (m, 1H, CHB-
CHA-3), 1.83–1.74 (m, 1H, CHB-CHA-3); 13C NMR (75 MHz,
DMSO, 808C): d¼173.1, 155.12, 136.6, 135.63, 128.80,
128.66,128.40, 128.26, 128.21, 128.06, 67.34, 67.13, 58.38,
55.84, 50.46, 35.5; MS (EI): m/z¼355.2 (Mþ1, (calcd. for
Mþ: 354.1), 377.2 (Mþ23); anal. calcd. for C20H20N2O4: C
67.7, H 6.2, N 7.9%; found: C 67.7, H 6.5, N 8.2.
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Asymmetric Aldol Reaction Using Immobilized Proline
FULL PAPERS
8.1; MS (EI): m/z¼567.0 (Mþ1, calcd. for Mþ: 566.3; anal.
calcd. for C27H46N4O7Si C 57.2, H 8.1, N 9.8%; found: C 57.4,
H 8.2, N 9.9%.
roomtemperature for 1 h. The solvent was evaporated and
the residue was purified by column chromatography (hexane/
AcOEt, 1:1) to furnish 12 as a white solid; yield: 610 mg
(100%). 1H NMR (300 MHz, CDCl3): d¼7.34–7.23 (m, 10H,
Ph), 5.23–5.01 (m, 4H, OCH2), 4.44–4.36 (m, 1H, H-4),
4.25–4.17 (m, 1H, H-2), 3.88–3.79 (m, 1H, H5B-H5A), 3.31–
3.21 (m, 1H, H5B-H5A), 2.61–2.48 (m, 1H, H2B-H2A), 2.00–
1.83 (m, 1H, H2B-CH2A), 1.23 (s, 9H, CH3); 13C NMR
(75 MHz, DMSO, 808C): d¼174.1, 159.4, 156.5, 137.8, 137.1,
129.5, 129.3, 129.2, 129.1, 128.8, 68.3, 59.4, 53.5, 50.8, 50.1,
37.8, 29.7; MS (EI): m/z¼476.8 (Mþ23, calcd. for Mþ:
453.2); anal. calcd. for C25H31N3O4: C 68.6, H 7.1, N 9.6%;
found: C 68.7, H 7.4, N 9.5%.
(2S,4S)-2-Carboxy-4-(3-
triethoxysilylpropylaminocarbonylamino)pyrrolidine
(11a)
To a solution of 10a (1.4 g, 3.0 mmol) in a mixture of cyclohex-
ene (0.54 mL, 17.3 mmol) and ethanol (30 mL) was added 10%
Pd/C (850 mg). The suspension was refluxed for 15 min and
then diluted with ethanol and filtered through Celiteꢁ. The sol-
id was washed with ethanol and the combined filtrate and
washings were concentrated to furnish 11a as a brown solid,
which was used without further purification due to the low sta-
1
bility of the product. H NMR (300 MHz, CDCl3): d¼4.79–
(2S,4S)-2-Carboxy-4-(tert-butylureido)pyrrolidine
(13)
4.36 (m, 1H), 3.99–3.71 (m, 1H), 3.76–3.57 (dt, 6H), 3.42–
3.28 (m, 2H), 3.08–3.02 (m, 2H), 2.52–2.11 (m, 2H), 1.49–
1.33 (m, 2H), 1.13 (t, 9H), 0.64–0.50 (m, 2H); MS (EI): m/
z¼378.3 (Mþ1, calcd. for Mþ: 377.2, 406.2 (Mþ þ2–23–18).
To a solution of 12 (350 mg, 0.78 mmol) in a mixture of cyclo-
hexene (0.29 mL, 4.35 mmol) and ethanol (13 mL) was added
10% Pd/C (223 mg). The suspension was refluxed during
15 min and then diluted with ethanol. After cooling at room
temperature, the solution was filtered through Celiteꢁ, washed
with ethanol and the solvent was removed under reduced pres-
sure yielding 13 quantitatively as a white solid. No purification
(2S,4S)-2-tert-Butylaminocarbonyl-4-(3-
triethoxysilylpropylaminocarbonylamino)pyrrolidine
(11b)
1
was possible due to the instability of the product. H NMR
To a solution of 10b (900 mg, 2.23 mmol) in a mixture of cyclo-
hexene ( 10 mL, 9.86 mmol) and ethanol (15 mL) was added
10% Pd/C (400 mg). The suspension was refluxed during 1 h
and then diluted with ethanol. After cooling at roomtempera-
ture, the solution was filtered through Celiteꢁ, washed with
ethanol and the solvent was removed under reduced pressure
yielding 11b quantitatively as a pale brown solid; yield:
958 mg (2.20 mmol). No purification was possible due to the in-
stability of the product. 1H NMR (300 MHz, CDCl3): d¼4.32–
4.22 (m, 1H), 3.99–3.88 (m, 6H), 3.45–3.24 (m, 3H), 3.21–3.10
(m, 1H), 2.52–2.46 (m, 1H), 2.33–2.45 (m, 1H), 1.87–1.73 (m,
3H), 1.3 (s, 9H), 1.2 (t, 9H), 0.77 (t, 2H); MS (EI): m/z¼432.3
(Mþ1, calcd. for Mþ: 431).
(300 MHz, DMSO): d¼4.87–4.85 (m, 1H, H-2), 4.52–4.47
(m, 1H, H-4), 4.4–4.2 (m, 3H, 3 NH), 4.03–3.99 (m, 1H,
H5B-H5A), 3.76–3.72 (m, 1H, H5B-H5A), 3.14–2.84 (m, 2H,
H-3), 1.95 (s, 9H, CH3); 13C NMR (75 MHz, DMSO):
d¼173.9, 159.4 , 61.4, 52.0, 50.8, 50.2, 41.2, 29.7; MS (EI):
m/z¼250.5 (Mþ23, calcd. for Mþ: 229.1); anal. calcd. for
C10H19N3O3: C 52.3, H 8.3, N 18.3%; found: C 52.4, H 8.2, N
18.6%.
General Procedure for the Catalytic Asymmetric
Aldol Reaction of Hydroxyacetone and Aldehydes
using l-Proline at Room Temperature
Same as ref.[2b] Yields, d.r., and ee values are reported in Ta-
ble 2.
General Procedure for Preparation of Supported
Catalysts
A proline derivative (11a or 11b) (100 mg) bearing a triethox-
ysilyl group in toluene (10 mL) was added to a suspension of
the inorganic support (1 g) in a mixture of toluene/water
(20 mL/20 mL). The mixture was refluxed for 24 h. The solid
was then filtered and washed with toluene to remove the re-
maining non-supported proline derivative. The pale solid was
dried under vacuum. The loading (0.52 mmol/g) of the result-
ing catalyst was calculated by elemental analysis based on ni-
trogen. Anal. found: C 11.0, H 2.2, N 2.2%.
General Procedure for the Catalytic Asymmetric
Aldol Reaction of Hydroxyacetone and Aldehydes
using MCM41-Pro at 908C
To a suspension of hydroxyacetone (1 mL) and Pro-MCM-41
(20% mol) in anhydrous DMSO or toluene (1.6 mL) was add-
ed the aldehyde (0.5 mmol). The reaction mixture was stirred
at 908C for 24–72 h. Then the catalyst was filtered, and
NH4Cl (sat)/AcOEt was added to the filtrate. The layers
were separated and the aqueous phase was extracted thor-
oughly with AcOEt. The combined organic phases were dried
(MgSO4), concentrated and purified by flash chromatography
to afford the pure aldol product. Yields, reaction times, d.r. and
ee values are reported in Table 2.
(2S4S)-1,2-Dibenzyloxycarbonyl-4-(3-tert-
butylureido)pyrrolidine (12)
To a solution of 9a (2.20 g, 6.21 mmol) in anhydrous CH2Cl2
(32 mL) was added tert-butyl isocyanate (208.89 g,
2.11 mmol). The reaction mixture was stirred under Ar at
Adv. Synth. Catal. 2005, 347, 1395–1403
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1401

´
´
Felix Calderon et al.
FULL PAPERS
General Procedure for the Catalytic Asymmetric
Aldol Reaction of Hydroxyacetone and Aldehydes
using l-Proline Assisted by MW Heating
(3S,4R)-4-Phenyl-3,4-dihydroxybutan-2-one (syn-25)
1H NMR (300 MHz, CDCl3): d¼7.4–7.2 (m, 5H, Ph), 5.01 (d,
1H, H-4), 4.40 (d, 1H, H-3), 1.96 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d¼209.1, 140.4, 128.2, 128.2, 81.0, 74.2,
26.7; Rt (GC, method: 1208C, 2 min, 58C/min): 15.4 min.
To a mixture of hydroxyacetone (0.25 mL), l-Pro (20% mol),
and anhydrous DMSO or toluene (1 mL) was added the alde-
hyde (0.5 mmol). Intermittent irradiation was applied: cycles
of 1 min under MW irradiation/2 min of magnetic stirring out-
side the oven. Then, NH4Cl and AcOEt were added. The layers
were separated and the aqueous phase was extracted thor-
oughly with AcOEt. The combined organic phases were dried
(MgSO4), concentrated and purified by flash chromatography
to afford the pure aldol product. Yields, reaction times, d.r. and
ee values are reported in Table 4.
(3S,4R,5S,6S)-7-O-Benzyl-5,6-O-isopropylidene-3,4-
dihydroxyheptan-2-one (anti-26)
Column chromatography (hexane/AcOEt, 5:1) yielded a col-
1
orless oil. H NMR (300 MHz, CDCl3): d¼7.4–7.2 (m, 5H,
Ph), 4.57 (s, 2H, CH2Bn), 4.3–4.1 (m, 3H, H-3, H-5, H-6),
3.8–3.5 (m, 3H, H-4, H-7), 2.31 (s, 3H, CH3), 1.44 and 1.41 (s,
6H, Ip); 13C NMR (75 MHz, CDCl3): d¼209.7, 137.7, 128.5,
127.9, 127.8, 110.0, 78.4, 78.3, 75.7, 73.7, 70.3, 70.2, 27.8,27.2,
26.9; MS (EI): m/¼325.2 (Mþ1, calcd. for Mþ: 324.1), 347.0
(Mþ23); anal. calcd. for C17H24O6: C 62.9, H 7.4%; found: C
63.3, H 7.8%; Rt (GC, method: 1208C, 2 min, 58C/min):
16.0 min.
General Procedure for the Catalytic Asymmetric
Aldol Reaction of Hydroxyacetone and Aldehydes
using MCM41-Pro Assisted by MW Heating
To a mixture of hydroxyacetone (1 mL), Pro-MCM-41 (20%
mol), and anhydrous DMSO or toluene (1.6 mL) was added
the aldehyde (0.5 mmol). Intermittent irradiation was applied:
cycles of 1 min under MW irradiation/2 min of magnetic stir-
ring outside the oven. Then the catalyst was filtered, and
NH4Cl (sat)/AcOEt was added to the filtrate. The layers
were separated and the aqueous phase was extracted thor-
oughly with AcOEt. The combined organic phases were dried
(MgSO4), concentrated and purified by flash chromatography
to afford the pure aldol product. Yields, reaction times, d.r. and
ee values are reported in Table 4.
(3S,4S,5S,6S)-7-O-Benzyl-5,6-O-isopropylidene-3,4-
dihydroxyhetan-2-one (syn-27)
1H NMR (300 MHz, CDCl3): d¼7.4–7.2 (m, 5H, Ph), 4.57 (s,
2H, CH2), 4.3–4.1 (m, 3H, H-3, H-5, H-6), 3.8–3.5 (m, 3H,
H-4, H-7), 2.28 (s, 3H, CH3), 1.44 and 1.41 (s, 6H, Ip); 13C
NMR (75 MHz, CDCl3): d¼208.2, 137.1, 128.6, 128.0, 127.9,
109.7, 78.5, 78.4, 75.7, 73.8, 70.3, 70.2, 27.1, 27.0, 25.5; Rt (GC,
method: 1208C, 2 min, 58C/min): 16.3 min.
(3S,4S,5R)-4-Azido-6-O-benzyl-3,4-dihydroxyhexan-2-
one (anti-28)
(3S,4S)-3,4-Dihydroxy-5-methylhexan-2-one (anti-22)
Column chromatography (hexane/AcOEt, 2:1) yielded a yel-
low oil. 1H NMR (300 MHz, CDCl3): d¼7.4–7.2 (m, 5H,
Ph), 4.57 (s, 2H, OCH2), 4.3–4.1 (m, 2H, H-3, H-4), 3.8–3.6
(m, 2H,CH2), 3.7 (s, 1H, H-5), 2.19 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d¼211.5, 137.3, 129.0, 128.9, 128.2, 77.8,
76.8, 74.0, 71.8, 61.1, 28.5; MS (EI): m/z¼280.2 (Mþ1, (calcd.
for Mþ: 279.12), 302.0 (Mþ23); anal. calcd. for C13H17N3O4: C
55.9, H 6.1, N 15.0%; found: C 55.9, H 6.3, N 14.8%. Rt (GC,
method: 1508C, 2 min, 58C/min): 14.2 min.
Column chromatography (hexane/AcOEt, 4:1) yielded a yel-
low oil. The spectral data (1H and 13C NMR) were identical
to those previously reported.[2b]
(3S,4S)-4-Cyclohexyl-3,4-dihydroxybutan-2-one (anti-
23)
Column chromatography (hexane/AcOEt, 3:1) yielded a yel-
low oil. The spectral data (1H and 13C NMR) were identical
to those previously reported.[2b]
(3S,4R,5R)-4-Azido-6-O-benzyl-3,4-dihydroxyhexan-
2-one (syn-29)
1H NMR (300 MHz, CDCl3): d¼7.4–7.2 (m, 5H, Ph), 4.57 (s,
2H, OCH2), 4.3–4.1 (m, H-3, H-4), 3.8–3.6 (m, 2H, CH2), 3.7
(s, 1H, H-5), 2.15 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d¼211.4, 136.64, 129.2, 128.5, 127.9, 76.7, 76.2,74.2, 71.3,
61.4, 28.1; Rt (GC, method: 1508C, 2 min, 58C/min): 14.9 min.
(3S,4S)-4-Phenyl-3,4-dihydroxybutan-2-one (anti-24)
Column chromatography (hexane/AcOEt, 3:1) yielded a col-
1
orless oil. H NMR (300 MHz, CDCl3): d¼7.4–7.2 (m, 5H,
Ph), 5.01 (d, 1H, JH3,H4 ¼4.5 Hz, H-4), 4.47 (d, 1H, H-3), 1.96
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d¼209.1, 139.4,
128.6, 128.2, 126.5, 81.48, 75.1, 27.9. MS (EI): m/z¼203.0
(Mþ23, (calcd. for Mþ: 180.08); anal. calcd. for C10H12O3: C
66.6, H 6.7%; found: C 66.7, H 6.9%; Rt (GC, method: 808C,
2 min, 58C/min): 15.3 min.
Acknowledgements
We thank Dr. A. Alcudia and Dr. F. Cortaza for their continuous
support. We also thank Prof. R. Riguera and Dr. F. Freire for
1402
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asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 1395–1403

Asymmetric Aldol Reaction Using Immobilized Proline
FULL PAPERS
their generous gifts of MPA and 9-AMA and helpful discus-
P. Arvidsson, Tetrahedron Asymmetry 2004, 15, 1831–
1834; g) A. Berkessel, B. Koch, J. Lex, Adv. Synth. Catal.
2004, 346, 1141–1146.
´
sions. The financial support by Ministerio de Educacion y Cien-
cia (Grants BQU001-1503, CTQ2004-03523/BQU and
MAT2003-07945-C02-02) is gratefully appreciated.
[4] For a complete overview of heterogenized catalyst, see:
a) R. A. Sheldon, H. van Bekkum, (Eds.), Fine Chemicals
through Heterogeneous Catalysis, Wiley-VCH, Weinheim,
2001; for examples of chiral catalysis, see: b) D. E. De Vos,
F. J. Vankejecom, P. A. Jacobs (Eds.), Chiral Catalyst Im-
mobilization and Recycling, Wiley-VCH, Weinheim,
2000; for examples of MCM-41, see: c) J. Y. Ying, C. P.
Mehnert, M. S. Wong, Angew. Chem. Int. Ed. 1999, 38,
56–77; d) A. Corma, Chem. Rev. 1997, 97, 2373–2419;
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