Hydrophobically directed aldol reactions: Polystyrene-supported L-proline as a recyclable catalyst for direct asymmetric aldol reactions in the presence of water

Article abstract of DOI:10.1002/ejoc.200700586

A simple synthetic methodology for the preparation of a polystyrene-supported L-proline material is reported, and this material has been used as catalyst in direct asymmetric aldol reactions between several ketones and arylaldehydes to furnish aldol produ

Full text of DOI:10.1002/ejoc.200700586

FULL PAPER
DOI: 10.1002/ejoc.200700586
Hydrophobically Directed Aldol Reactions: Polystyrene-Supported -Proline as
L
a Recyclable Catalyst for Direct Asymmetric Aldol Reactions in the Presence
of Water
[
a]
[a]
[a]
Michelangelo Gruttadauria,* Francesco Giacalone, Adriana Mossuto Marculescu,
[a]
[a]
[a]
Paolo Lo Meo, Serena Riela, and Renato Noto
Dedicated to Professor Domenico Spinelli on the occasion of his 75th birthday
Keywords: Alcohols / Enantioselectivity / Ketones / Organocatalysis / Polymers
A simple synthetic methodology for the preparation of a poly-
styrene-supported -proline material is reported, and this
plained in terms of the formation of a hydrophobic core in
the inner surface of the resin, whereas the hydrophilic pro-
line moiety lies at the resin/water interface. Such a microen-
vironment both promotes the aldol reaction and increases the
stereoselectivity. Recycling investigations have shown that
this material can be reused, without loss in levels of conver-
sion and stereoselectivity, for at least five cycles.
L
material has been used as catalyst in direct asymmetric aldol
reactions between several ketones and arylaldehydes to fur-
nish aldol products in high yields and stereoselectivities.
Screening of solvents showed that these reactions take place
only in the presence of water or methanol, at lower levels of
conversion in the latter case. This solvent effect, coupled
with the observed high stereoselectivities, has been ex-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
aldolase enzymes,[16] promoting the formation of an en-
amine and its enantioselective condensation with an aldol
Introduction
In the last decade organocatalysis has became a field of acceptor. Such -proline-catalyzed aldol reactions are usu-
[
1]
great interest. Organocatalysts are metal-free small or- ally carried out in organic solvents such as DMSO, DMF,
ganic molecules that are able to function as efficient and or chloroform. The extent of enantioselectivity in the reac-
selective catalysts for a large variety of enantioselective tion was found to be dependent on the solvent system used;
transformations. In this context, -proline and its deriva- dimethyl sulfoxide was reported to be the solvent of
tives have emerged as powerful organocatalysts.[ -Proline choice.
2]
[4a]
However, the recovery of the catalysts and the
can be regarded as the simplest “enzyme” and it has been separation of the products are major disadvantages in the
successfully applied in many reactions, such as Robinson homogeneous catalytic process. Moreover, the organocata-
[
3]
[4]
[5]
annulations,
aldol reactions,
Mannich reactions,
lyst is usually used in substantial quantity, in the case of -
[
6]
8]
[7]
Michael reactions, direct electrophilic α-aminations, Di- proline up to 30 mol-%. For this reason efficient recovery
els–Alder reactions, Baylis–Hillman reactions, aza-Mor- and reuse of the organocatalyst have became major con-
[
[9]
[10]
[11]
[17]
ita-Baylis–Hillman reactions,
α-selenenylation,
oxi- cerns.
dation, chlorination, and others.[14]
[
12]
[13]
Several methods for -proline recovery have been investi-
Among all these processes, -proline-mediated aldol re-
actions affording β-hydroxy ketones have been investigated
in great depth. Indeed, the aldol reaction is one of the most
important C–C bond-formation methods in organic synthe-
sis.[ Proline and its derivatives operate by bifunctional ca-
talysis and play the role of a simplified version of the type I
gated. Immobilization by adsorption on silica gel gave poor
[4b]
enantiomeric excess values,
but good results have been
reported for the use of -proline in ionic liquids as reusable
[18]
catalysts for aldol reactions.
BmimPF was the ionic li-
6
15]
quid of choice, though recycling studies showed slightly di-
minished yields and ee values. Excellent results were ob-
[
19]
tained in the cross-aldol reaction. More recently, an ionic
liquid-anchored (2S,4R)-4-hydroxyproline was prepared.[
20]
[
a] Dipartimento di Chimica Organica “E.Paternò”, Università di This molecule catalyzed the direct asymmetric aldol reac-
Palermo,
tion in neat acetone or butan-2-one with enantioselectivity
superior to that afforded by -proline. The catalyst was eas-
ily recovered and reused for at least four times with un-
Viale delle Scienze, Pad. 17, 90128 Palermo, Italy
Fax: +39-091-596825
E-mail: mgrutt@unipa.it
4688
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Eur. J. Org. Chem. 2007, 4688–4698

Polystyrene-supported -Proline as a Catalyst in Asymmetric Aldol Reactions
changed results. Recycling of proline and solvent was pos- ing with asymmetric aldol reactions in water based on the
sible over up to ten runs without loss of activity when the use of a polystyrene-supported proline. The -proline was
reaction was carried out in PEG-400.[
21]
anchored to a polystyrene resin through a 1,2,3-triazole
We have reported the use of supported ionic liquids as moiety and this catalyst was used for the aldol reaction in
new recyclable materials for the -proline-catalyzed aldol water, giving high stereoselectivities, whereas yields were in-
[
22]
reaction.
liquid-modified silica gel with or without additional ad-
sorbed ionic liquid. These catalytic systems gave good yields order to obtain the polystyrene-supported -proline. Com-
and ee values and were easily recovered and reused. mercially available trans-N-Boc-4-hydroxy--proline was
In our case, proline was adsorbed onto ionic creased by using 10 mol-% of DiMePEG as additive.
In our case a different synthetic strategy was followed in
In addition to these examples, -proline was also an- used for proline immobilization since its hydroxy group can
chored to a support. Good yields and ee values were ob- be easily functionalized. As support we chose the commer-
tained with polyethylene glycol supported proline.[ Up to cially available mercaptomethyl-functionalized polymer
four cycles were reported with unchanged ee values, but in shown in Scheme 1 (1% cross-linked with DVB, spherical
slowly diminishing yields. Low ee values were observed in beads, particle size 100–200 mesh, 2.5 mmol per gram load-
reactions with proline immobilized on polyethylene glycol ing). Anchorage of -proline was accomplished in two steps
grafted onto cross-linked polystyrene in aqueous media, (Scheme 1): (1) synthesis of hydroxy--proline styrene deriv-
while higher ee values were obtained with polymer-sup- ative 1 and (2) radical reaction between the polystyrene and
23]
[
24]
ported peptide.
Proline immobilized on a mesoporous 1 followed by deprotection of the proline moiety. The re-
support was used in asymmetric aldol reactions of hy- moval of the tert-butoxycarbonyl group was carried out
droxyacetone with aldehydes.[
25]
with TFA/CH Cl2 (20:80), followed by treatment with
2
These reactions, under both homogeneous and hetero- Et N/MeOH (2:98).
3
geneous conditions, are usually carried out in DMSO,
DMF, acetone, chloroform, and Ϫ in selected examples Ϫ
in DMSO/H O or DMF/H O. Indeed, addition of water
2
2
may improve enantioselectivities.[ However, the use of a
26]
large amount of water resulted in the formation of products
with low or no enantioselectivity.[
4b,27]
Recently, highly dia-
stereo- and enantioselective direct aldol reactions in water
in the presence of proline bearing large apolar substituents
or amine catalysts bearing hydrophobic alkyl chains have
[
28]
been reported.
Such molecules are better mimics than
unmodified proline since natural Class I aldolase enzymes
use an enamine mechanism in water. The authors hypothe-
sized that these catalysts should assemble with hydrophobic
reactants in water and sequester the transition state from
water.
Since the substrates are insoluble in water, a debate is
now open as to whether some of these reactions really are
[
29]
“all wet”.
Hayashi has proposed that these reactions
Scheme 1. Synthesis of the polystyrene-supported -proline cata-
lyst.
might be better considered as carried out “in the presence
[
30]
of water”.
On the other hand, Blackmond has raised
doubts about the greenness of organocatalytic reactions
This procedure gave the polystyrene-supported -proline
carried out in the presence of water.[
31]
in high yield and in a very simple way (proline loading ca.
–1
In this context, our research is addressed towards two 1.4 mmolg , as determined by elemental analysis and
major objectivies: (1) the synthesis of a polystyrene-sup- weight gain). The resin was characterized by elemental
13
ported -proline and its use as an enzyme-like catalyst in analysis and solid state C NMR and IR spectroscopy. Fig-
the direct asymmetric aldol reaction in the presence of ure 1 shows the 13C MAS NMR spectrum of N-Boc-pro-
13
water and (2) recycling investigations into such hetero- tected resin 2, while Figures 2 and 3 show C MAS NMR
geneous catalytic materials.
and IR spectra, respectively, of deprotected resin 2. The
presence of signals in the aliphatic region confirmed the
anchorage of the proline moiety. Moreover, a comparison
between 13C MAS NMR spectra before and after deprotec-
tion showed the almost complete disappearance of the Boc
Results and Discussion
We had previously reported preliminary results on the group at δ = 29 ppm and the IR spectrum showed the typi-
use of a polystyrene-supported -proline as an efficient and cal pattern of an amino acid. Figure 4 shows a SEM micro-
recyclable catalyst both for enantioselective aldol reactions graph of resin 2.
in water without additives and for α-selenenylation of alde-
hydes. Recently, Pericàs et al. published a paper deal- ditions used by Hayashi
As a first approach we tested our catalyst under the con-
[
32]
[33]
[28b]
(aldehyde 0.4 mmol; cyclohexa-
Eur. J. Org. Chem. 2007, 4688–4698
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4689

M. Gruttadauria et al.
FULL PAPER
Figure 1. 13C MAS NMR spectrum of N-Boc-protected resin. Side
bands (x).
Figure 4. SEM micrograph of polystyrene-supported proline 2.
none 2.0 mmol; catalyst 0.04 mmol; H O 0.14 mL), using p-
2
cyanobenzaldehyde as acceptor (Table 1, Entry 1). The re-
action worked nicely in the presence of water, giving the
aldol product in almost quantitative yield and with high
diastereoselectivity and high ee value. The use of larger
amounts of water (200 or 400 µL; Table 1, Entries 2 and 3)
yielded the aldol product with decreased levels of conver-
sion, but still with high diastereoselectivity and ee value.
Very interestingly, the reaction did not work in the absence
of water (Table 1, Entry 4).
This results prompted us to investigate the solvent effect
on the aldol reaction (Table 2). A solvent screening gave
interesting results. The reaction did not work either in polar
aprotic solvents (DMSO, DMF; Table 2, Entries 1 and 2)
or in apolar solvents (dioxane, chloroform; Table 2, En-
tries 3 and 4). The use of polar protic solvents (MeOH,
EtOH, i-PrOH; Table 2, Entries 6–8) showed decreased
Figure 2. 13C MAS NMR spectrum of resin 2. Side bands (x).
Figure 3. IR spectrum of resin 2.
690
4
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Eur. J. Org. Chem. 2007, 4688–4698

Polystyrene-supported -Proline as a Catalyst in Asymmetric Aldol Reactions
Table 1. The effect of amount of water on the reaction yield and lent levels of conversion were observed in the other cases.
[
a]
selectivity.
Diastereoselectivities (antiϾsyn) and enantioselectivities
were excellent in all cases except for that of furaldehyde, for
which a lower diastereoselectivity was observed (85:15). It
is interesting to note that aliphatic aldehydes did not react
(Table 3, Entries 14–16).
Next, we examined reactions between different ketones
Entry Water
µL]
Time
[h]
Conv.
[%]
Yield anti/syn[b]
[%]
ee[c]
[%]
and aldehydes. Reactions between cyclopentanone and p-
cyano- or p-nitrobenzaldehyde gave the expected aldol
products in excellent yields, and with diasteromeric ratios
comparable with those observed with unsupported proline
[
1
2
3
4
140
200
400
0
22
22
22
22
98
80
67
93
76
64
–
95:5
95:5
96:4
nd
98
98
98
nd
[
28a,35]
in aqueous media
and good ee values (Table 4, En-
Ͻ5
tries 1 and 2). Again, in the absence of water, the reaction
did not take place (Table 4, Entry 3). The reaction did not
[
a] Reaction conditions: cyclohexanone (207 µL, 2.0 mmol), alde-
hyde (0.4 mmol), catalyst (0.04 mmol), H O at room temperature.
2
[
b] Determined by 1H NMR spectroscopic analysis of the crude take place with cycloheptanone (Table 4, Entry 4) and so
product. [c] Determined by HPLC using a chiral column.
we tried different reaction conditions. We were delighted to
find that the reaction worked nicely in chloroform/water as
levels of conversion on going from methanol to i-PrOH. In reaction medium.
methanol, stereoselectivity was comparable with that ob-
Tetrahydro-4H-pyran-4-one gave excellent levels of con-
served in water, while lower diastereoselectivity was ob- version but lower stereoselectivity (Table 4, Entry 6). The
served in ethanol.
lower ee value may be ascribed to the increased water solu-
bility of the ketone. In the case of tetrahydro-4H-thiopyran-
Table 2. Solvent effect on the aldol reaction between cyclohexanone
4-one the usual reaction conditions gave low levels of con-
and p-nitrobenzaldehyde.[
a]
version (11%, Table 4, Entry 7) since this ketone is solid at
room temperature The reaction carried out in DMSO/water
(170 µL/40 µL) gave the expected aldol with poor levels of
conversion (33%; Table 4, Entry 8). Searching for optimiza-
tion conditions we found that the reaction worked well in
chloroform as solvent with a stoichiometric amount of
water (7 µL, Table 4, Entry 9). We therefore again carried
out the reaction between cyclohexanone and p-nitrobenzal-
dehyde, but in the presence of only 7 µL of water (Table 4,
Entry 10), and found that such conditions furnished the al-
dol product in high levels of conversion and with excellent
stereoselectivity.
The reaction with acetone was carried out with use of a
large amount of ketone. In fact, with the usual amount of
ketone very poor levels of conversion was obtained because
of the high solubility of acetone in water. The levels of con-
Entry Solvent
Time Conv. Yield anti/syn[b] ee[c]
[h]
[%]
[%]
[%]
1
2
3
4
5
6
7
8
9
1
DMSO
DMF
dioxane
22
22
22
22
22
22
22
22
22
22
nr
nr
nr
nr
85
42
12
nr
47
48
–
–
–
–
–
–
–
–
–
CHCl
3
–
–
–
H
2
O
82
40
10
–
44
44
95:5
95:5
88:12
–
96:4
97:3
98
95
nd
–
98
98
MeOH
EtOH
iPrOH
DMSO/H
3 2
CHCl /H O
[
d]
2
O
[
d]
0
[
a] Reaction conditions: cyclohexanone (207 µL, 2.0 mmol), alde- version was increased up to 28% by use of a 25:1 acetone/
hyde (0.4 mmol), catalyst (0.04 mmol), solvent (140 µL) at room aldehyde molar ratio (Table 4, Entry 11). However, the ee
1
temperature. [b] Determined by H NMR spectroscopic analysis of
value was lower than that obtained under homogeneous
the crude product. [c] Determined by HPLC using a chiral column.
conditions, again probably because of the solubility of ace-
3 2
[d] DMSO or CHCl 120 µL, H O 20 µL.
tone in water. In order to check whether enantioselectivity
In order to ascertain the crucial role played by water, might be increased, we carried out the reaction in the ab-
we carried out the reaction both in DMSO/water and in sence of water. The level of conversion was indeed slightly
chloroform/water. In both cases the reaction took place higher, whereas the ee value was good (Table 4, Entry 12).
with excellent stereoselectivity, although at lower levels of Moreover, it should be pointed out that in this case the
conversion. Water thus appears to be the optimal medium reaction took place in the absence of water. Then we investi-
for the reaction even if substrates are not soluble.
gated the behavior of butan-2-one under the same condi-
Next, a representative set of aldehydes was examined. Re- tions as used in the reaction with acetone. Good levels of
actions were carried out in the presence of water. Interest- conversion were observed using a 25:1 ketone/aldehyde mo-
ingly, aromatic aldehydes gave excellent results, with reac- lar ratio. The regioselectivity was low, but high diastereo-
tion times ranging between 22 and 120 h. Low levels of con- selectivity was observed. The reaction carried out in the ab-
versions were observed only in the cases of the more steri- sence of water gave low levels of conversion. Moreover, low
cally hindered β-naphthaldehyde and the less reactive p-tol- regioselectivity and no diastereoselectivity were observed.
ualdehyde. In the latter case, the slightly lower ee value ob-
Finally, we carried out recycling studies (Table 5). The
served may be due to electronic factors.[ Good-to-excel- reactions were carried out on larger scales (aldehyde
34]
Eur. J. Org. Chem. 2007, 4688–4698
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M. Gruttadauria et al.
FULL PAPER
Table 3. Direct asymmetric aldol reactions between cyclohexanone
Table 4. Direct asymmetric aldol reactions between ketones and al-
dehydes in the presence of water, catalyzed by resin 2 (10 mol-%).
[
a]
and aldehydes in the presence of water, catalyzed by resin 2
[
a]
(10 mol-%).
[
a] Reaction conditions: ketone (2.0 mmol), aldehyde (0.4 mmol),
catalyst (0.04 mmol), H O (140 µL) at room temperature. [b] Deter-
2
1
mined from H NMR spectroscopic analysis of the crude product.
[c] Determined by HPLC using a chiral column. [d] Without water.
[e] CHCl /H O 100 µL/40 µL. [f] DMSO/H O 170 µL/40 µL. [g]
[
a] Reaction conditions: cyclohexanone (207 µL, 2.0 mmol), alde-
hyde (0.4 mmol), catalyst (0.04 mmol), H O (140 µL) at room tem-
perature. [b] Determined by H NMR spectroscopic analysis of the
crude product. [c] Determined by HPLC using a chiral column.
2
3
2
2
1
3 2
CHCl /H O 140 µL/7 µL. [h] Ketone/aldehyde molar ratio 25:1.
[i] Regioisomeric ratio.
4692
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Polystyrene-supported -Proline as a Catalyst in Asymmetric Aldol Reactions
2
mmol), the resin was used five times with cyclohexanone
and p-nitrobenzaldehyde, and the reactions were quenched
by filtration. After each cycle the resin was washed with
EtOAc and methanol and was then dried under vacuum at
room temperature for a few minutes. Each cycle gave excel-
lent anti/syn ratios and ee values. Moreover, after five cycles
no decrease in levels of conversion was observed.[
36]
Table 5. Recycling studies.[a]
Scheme 2. Mechanism for the -proline-catalyzed aldol reaction.
Entry Cycle
Time
h]
Conv.
[%]
Yield
[%]
anti/syn[b]
ee[c]
[%]
[
We hypothesize that the hydrophilic proline moiety lies
1
2
3
4
5
1
2
3
4
5
22
22
22
22
22
85
79
82
85
88
82
77
80
84
85
95:5
95:5
95:5
95:5
95:5
98
98
98
98
98
at the interface (resin/H O), which facilitates the formation
2
of a hydrophobic core on the inner surface of the resin (Fig-
ure 5). Such a microenvironment promotes the aldol reac-
[
40]
tion with high stereoselectivity.
even a stoichiometric amount of water seems to promote
O (700 µL) at room the aldol reaction in high yield and stereoselectivity. The
It is worth noting that
[
a] Reaction conditions: cyclohexanone (1.035 mL, 10.0 mmol), al-
dehyde (2.0 mmol), catalyst (0.2 mmol), H
2
1
temperature. [b] Determined by H NMR spectroscopic analysis of
the crude product. [c] Determined by HPLC using a chiral column.
different reaction rates observed when the reactions are car-
ried out in pure cyclohexanone or in acetone are ascribed
to the fact that cyclic ketones react much more slowly in
From a mechanistic point of view the crucial role played
by water deserves more thorough comment. Such a role was
evident when the reaction was carried out under neat condi-
tions (Table 1, Entry 4). Indeed, in contrast with the data
reported by Pericás, water seems to be essential. Apart from
water, only methanol was able to promote the reaction. Ex-
perimental evidence indicates that water influences the reac-
[2c,4a,4b,4l]
the proline-catalyzed aldol reactions.
[
37]
tion rate.
Acceleration of organic reactions through
[
38]
aqueous solvent effects is a well known phenomenon.
Water may play several roles in the proline-catalyzed aldol
process: it might assist in the hydrolysis of the intermediate
oxazolidinones that might be forming from the aldehyde,
ketone, or the product. Alternatively, water might promote
faster hydrolysis of the intermediates of the enamine cata-
lytic cycle (Scheme 2).[
4e,26,39]
Moreover, a small excess of
water facilitates proton transfer in the transition state, low- Figure 5. Proposed structure of the polystyrene-supported proline
ering the LUMO of the incoming electrophile.[4e] However,
in the presence of water.
it should be remembered that beneficial effects of water
molecules are observed when water is added as cosolvent
Under homogeneous conditions, the reaction usually
up to 300 mol-%. The use of larger amounts of water usu- yields the aldol product in low diastereomeric ratio. For ex-
ally gives racemic products. In our case, the polystyrene- ample, the reaction between cyclohexanone and p-ni-
supported proline behaves as a proline substituted with a trobenzaldehyde in DMSO gave a 63:37 anti/syn ratio.[
28a]
large apolar substituent, allowing its use in water.
When the reaction was carried out with modified -proline
On the other hand, the fact that no reaction is observed in the presence of water the diastereoselectivity ratio was as
[
28b]
in DMSO or DMF is very unusual. We believe that solvents high as 95:5.
In our case the high diastereomeric ratios
reported in Table 2 do not promote the reaction simply be- observed can be explained as depicted in Figure 6. Quan-
cause they are good solvents. Ketones and aldehydes are tum mechanical calculations have predicted the transition
well dissolved, while the catalytic center is supported on a state geometries for the reaction of cyclohexanone enamine
[
41]
material having a very low surface area. This strongly favors with benzaldehyde.
Following this mechanism we hy-
the repartition of the reactants in the liquid phase. When pothesize that transition state A is highly stabilized because
water is used as reaction medium, reactants are forced into the hydrophobic aldehyde lies in the inner hydrophobic re-
the hydrophobic pocket of the resin. In other words, the gion, while transition state B is destabilized because the
reaction proceeds in a concentrated organic phase.
hydrophobic part of the aldehyde is directed towards the
Eur. J. Org. Chem. 2007, 4688–4698
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4693

M. Gruttadauria et al.
FULL PAPER
outer hydrophilic region. Such hydrophobic interactions drophilic outer region force hydrophobic aryl aldehydes
have been used to explain improved selectivities on transi- into the restricted hydrophobic inner pocket. In this way
tion from organic to aqueous solvents.[
42]
water promotes the reaction and increases the stereoselec-
tivity. In this sense, our material can be considered a better
mimic of natural class I aldolase enzymes, which use an en-
amine-mediated mechanism in water. Finally, recycling in-
vestigations confirmed the usefulness of this catalytic mate-
rial, which can be easily recovered by simple filtration and
reused after few minutes in subsequent cycles without loss
in activity. This polystyrene-supported -proline is currently
being used as a catalyst in other -proline-catalyzed reac-
tions, and further applications and improvements will be
presented in the due course.
Experimental Section
NMR spectra were recorded with a Bruker 300 MHz spectrometer
1
3
3
in CDCl as solvent. Solid-state C MAS NMR spectra were re-
corded with a Bruker AV 400, 400 MHz spectrometer with samples
packed in zirconia rotors spinning at 5 kHz. FTIR spectra were
recorded with a Shimadzu FTIR 8300 infrared spectrophotometer.
Carbon and nitrogen contents were determined by combustion
analysis in a Fisons EA 1108 elemental analyzer. Optical rotations
were measured in chloroform with a Jasco P1010 polarimeter. Chi-
ral HPLC analyses were performed with a Shimadzu LC-10AD
apparatus equipped with a SPD-M10A UV detector and Daicel
columns (OD-H, AD-H, AS-H) with hexane/isopropyl alcohol as
eluent. Aldol products, except for (S)-2-[(R)-(3-chlorophenyl)(hy-
droxy)methyl]cyclohexanone (Table 3, Entry 4) and (S)-2-[(R)-hy-
droxy(perfluorophenyl)methyl]cyclohexanone (Table 3, Entry 12),
are known compounds (see Table 6 and footnotes) and showed
spectroscopic and analytical data in agreement with their struc-
Figure 6. Proposed transition state model for the major stereoiso-
mer (A) and the minor stereoisomer (B).
With a more hydrophobic aldehyde, such as pentafluo-
robenzaldehyde, higher diastereoselectivity was observed,
while lower diastereoselectivity was observed with the more
hydrophilic furfuraldehyde. Moreover, lower stereoselectivi-
ties were observed with more hydrophilic ketones such us
pyran-4-one or acetone. When acetone was used without
water, the enantioselectivity was higher. A similar result can
be seen in the case of butan-2-one. When the reaction was tures. Configurations of products were assigned by comparison
performed without water no diastereoselectivity was ob- with literature data (Table 6). Configurations of new products were
assigned by analogy.
served (Table 4, Entry 14), while excellent diastereoselectiv-
ity was observed in the presence of water (Table 4, En- (2S,4R)-1-(tert-Butoxycarbonyl)-4-(4-vinylbenzyloxy)pyrrolidine-2-
try 13).
carboxylic Acid (1): A solution of trans-Boc-4-hydroxy--proline
2.0 g, 8.65 mmol) in anhydrous THF (30 mL) was added dropwise,
under argon, at 0 °C to a suspension of NaH (60% mineral oil,
51 mg, 18.77 mmol) in anhydrous THF (20 mL). The mixture was
stirred at r.t. for 1 h, and 18-crown-6 (228 mg, 0.86 mmol) and 4-
chloromethylstyrene (90%, 3.66 g, 21.6 mmol) were then added.
The mixture was stirred for 1 h at r.t., and then at 50 °C overnight.
After cooling to r.t., water (100 mL) was added. The aqueous phase
was extracted with cyclohexane (2ϫ250 mL) in order to remove
the unreacted 4-chloromethylstyrene. The aqueous phase was acidi-
(
7
Conclusions
In summary, we have prepared a polystyrene-supported
-proline material by a simple synthetic methodology that
yields the resin in two steps starting from commercially
available mercaptomethyl-polystyrene. This material has
been used as catalyst in direct asymmetric aldol reactions
between several ketones and aryl aldehydes, without addi-
tives, to furnish aldol products in high yields and with ste-
fied at pH 2–3 by adding a solution of KHSO
extracted with ethyl acetate (3ϫ100 mL). The organic phase was
dried (MgSO ) and concentrated under reduced pressure to give
4
(2 ), and was then
4
2
8
reoselectivities (diastereoselectivities up to 99:1, ee values compound 1 as a pale yellow, viscous oil (2.151 g, 84%). [α]
up to 98%) comparable to or even better than those ob- –61.0 (c = 0.60, CHCl
=
D
1
3 3
). H NMR (300 MHz, CDCl ): δ = 1.45 (s,
served under homogeneous conditions. Investigations into 9 H), 2.05–2.50 (m, 2 H, 3-H), 3.60–3.78 (m, 2 H, 5-H), 4.15–4.25
(
1
6
m, 1 H, 4-H), 4.37–4.60 (m, 3 H, 2-H and CH
2
O), 5.25 (d, J =
0.8 Hz, 1 H, HHC=CH), 5.75 (d, J = 17.6 Hz, 1 H, HHC=CH),
.72 (dd, J = 10.8 and 17.6 Hz, 1 H, HHC=CH), 7.28 and 7.40 (d,
the reaction between cyclohexanone and p-nitrobenzalde-
hyde showed, unexpectedly, that solvents such as DMSO,
DMF, CHCl , or dioxane did not promote the reaction.
3
1
3
J = 8.1 Hz, each 2 H, ArH), 10.22 (br. s, 1 H, OH) ppm. C NMR
75 MHz, CDCl ): (two rotamers): δ = 28.2, 28.3, 35.1, 36.6, 51.4,
2.0, 58.1, 70.7, 70.9, 76.0, 76.6, 80.6, 81.0, 113.9, 114.5, 126.3,
26.5, 127.8, 128.8, 136.2, 136.4, 137.2, 137.3, 154.1, 155.4, 176.7,
Water was able to promote the reaction variously as the sole
reaction medium, or in mixtures with other solvents, or
even in stoichiometric amounts. Protic solvents showed
decreased levels of conversion along the series
(
3
5
1
1
–1
78.0 ppm. IR (liquid film): ν˜ = 3450, 2626, 1700, 1674, 1418 cm .
H OϾMeOHϾEtOHϾiPrOH. A model for these solvent C19H25NO (347.41): calcd. C 65.69, H 7.25, N 4.03; found C
2
5
effects has been proposed. Water molecules lying in the hy- 65.77, H 7.33, N 4.10.
694
4
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4688–4698

Polystyrene-supported -Proline as a Catalyst in Asymmetric Aldol Reactions
Polystyrene-Supported
was added (0.965 g, 2.4 mmol) to a degassed solution of compound
(2.515 g, 7.24 mmol) and AIBN (0.024 g, 0.145 mmol) in toluene
30 mL). The mixture was stirred at 110 °C overnight under argon.
After cooling to r.t. the resin was filtered and washed with toluene
and acetonitrile. A brilliant yellow resin was obtained (1.99 g).
From the weight increase (1025 mg) it was calculated that
L
-Proline (2): Mercaptomethyl polystyrene
ethyl ether (100 mL). The brilliant yellow resin was dried at 40 °C
for 24 h (1.54 g). The weight difference corresponds to the amount
of Boc removed, which is identical to the amount of available pro-
1
(
–
1
1 3
line (2.2 mmol/1.54 g = 1.43 mmol g ). C MAS NMR
(400 MHz): δ = 30.6, 40.0, 59.7, 128.0, 145.2, 185.5 ppm. IR: ν˜ =
3410, 3060, 3024, 2918, 2850, 1944, 1904, 1631, 1512, 1492, 1450,
–
1
1360, 1202, 1079, 1016, 820, 753, 696 cm . Elemental analysis
found: C 75.41, H 7.06, N 1.96, S 4.51.
2.94 mmol of monomer has been covalently attached to the resin.
The higher content with respect to the mercaptomethyl groups may
1
3
be ascribed to the formation of short polystyrenic chains. C MAS
NMR (400 MHz): δ = 28.8, 40.5, 59.1, 128.5, 145.2, 185.5 ppm.
IR: ν˜ = 3438, 3053, 3027, 2980, 1940, 1904, 1748, 1701, 1512, 1397,
Typical Procedure for Aldol Reaction: Catalyst 2 was added
(
0.04 mmol) to a mixture of the corresponding aldehyde (0.4 mmol)
and ketone (2.0 mmol) in distilled water (0.14 mL), and the reac-
tion mixture was stirred at r.t. The reaction was quenched by add-
ing ethyl acetate and, upon filtration, the catalyst was washed thor-
oughly with ethyl acetate and methanol. The organic layers were
collected and, after evaporation of solvent, the crude product was
–1
1
7
363, 1156, 1084, 819, 757, 699 cm . Elemental analysis found: C
5.54, H 7.25, N 1.96, S 4.00.
A portion of this resin (1.76 g) was suspended in dichloromethane/
trifluoroacetic acid (8 mL/2 mL). The resin became red and was
stirred at r.t. for 3 h. After this period, the resin was filtered and
1
checked by H NMR spectroscopy and HPLC, and was then puri-
washed with MeOH/Et
3
N 98:2 (100 mL), water (100 mL), and di-
fied by chromatography (petroleum ether/ethyl acetate).
1
Table 6. Selected H NMR spectroscopic data for diastereoisomers and HPLC data for enantiomers.
Eur. J. Org. Chem. 2007, 4688–4698
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4695

M. Gruttadauria et al.
FULL PAPER
Table 6. (Continued)
[
a] Ref.[28a] [b] Ref.[43] [c] Ref.[44] [d] Ref.[45] [e] Ref.[46] [f] Ref.[28b] [g] Ref.[47] [h] Ref.[35] [i] Ref.[48] [j] Ref.[27d]
(
S)-2-[(R)-(3-Chlorophenyl)(hydroxy)methyl]cyclohexanone: Yield:
(S)-2-[(R)-Hydroxy(perfluorophenyl)methyl]cyclohexanone: Yield
8.7 mg, 72%. M.p. 38–40 °C. [α]2
5
= +16.20 (c = 1.16, CHCl
): δ = 1.20–1.30 (m, 1 H), 1.43–1.75
m, 4 H), 1.99–2.07 (m, 1 H), 2.23–2.55 (m, 3 H), 3.93 (s, 1 H), 4.70
d, J = 8.7 Hz, 1 H), 7.08–7.23 (m, 4 H) ppm. 13C NMR (75 MHz,
): δ = 24.7, 27.7, 30.8, 42.7, 57.2, 74.3, 125.3, 127.1, 128.1,
).
103.6 mg, 88%. M.p. 85–87 °C. [α]
25
= –14.99 (c = 1.78, CHCl
6
D
3
D
3
).
1
1
H NMR (300 MHz, CDCl
3
H NMR (300 MHz, CDCl ): δ = 1.23–1.38 (m, 1 H), 1.55–1.74
3
(
(
(m, 3 H), 1.81–1.89 (m, 1 H), 2.08–2.16 (m, 1 H), 2.31–2.44 (m, 2
H), 2.47–2.54 (m, 1 H), 2.95–3.05 (m, 1 H), 4.28 (brs, 1 H), 5.31
1
3
CDCl
29.6, 134.3, 143.0, 215.3 ppm. IR (film): ν˜ = 3442, 1696 cm
15ClO (238.71): calcd. C 65.41, H 6.33; found C 65.55, H
.35 (Table 3, Entry 4).
3
(d, J = 9.6 Hz, 1 H) ppm. C NMR (75 MHz, CDCl
27.9, 30.5, 42.7, 54.6, 66.3, 114–148 (multiplet, C ), 214.5 ppm.
(294.22): calcd. C
53.07, H 3.77; found C 53.17, H 3.78 (Table 3, Entry 12).
3
): δ = 24.9,
–
1
1
C
6
4
.
6 5
F
–
1
13
H
2
11 5 2
IR (Nujol): ν˜ = 3411, 1706 cm . C13H F O
696
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4688–4698

Polystyrene-supported -Proline as a Catalyst in Asymmetric Aldol Reactions
hedron Lett. 2005, 46, 8899–8903; c) J. E. Imbriglio, M. M. Vas-
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Eur. J. Org. Chem. 2007, 4688–4698