A modular approach to catalyst hydrophobicity for an asymmetric aldol reaction in a biphasic aqueous environment

Article abstract of DOI:10.1039/b812607k

Catalyst 5, an ion pair consisting of a hydrophilic cation and a lipophilic anion, fulfils the solubility requirements needed to couple efficiency (enantioselectivities and anti-diastereoselectivities up to ≥99%) and catalyst recyclability in asymmetric aldol reactions under aqueous biphasic conditions.

Full text of DOI:10.1039/b812607k

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A modular approach to catalyst hydrophobicity for an asymmetric aldol
reaction in a biphasic aqueous environment†
Marco Lombardo,* Srinivasan Easwar, Alessandro De Marco, Filippo Pasi and Claudio Trombini*
Received 22nd July 2008, Accepted 19th August 2008
First published as an Advance Article on the web 29th September 2008
DOI: 10.1039/b812607k
Catalyst 5, an ion pair consisting of a hydrophilic cation and a lipophilic anion, fulfils the solubility
requirements needed to couple efficiency (enantioselectivities and anti-diastereoselectivities up to
≥99%) and catalyst recyclability in asymmetric aldol reactions under aqueous biphasic conditions.
A recent contribution by Jung and Marcus provides an inter-
esting theoretical basis to the effect of water in heterogeneous
reactions.9
Introduction
A milestone in the field of organocatalysis is represented by the
proline-catalyzed direct asymmetric intermolecular aldol reaction,
developed by List et al. in 2000.1 The reaction of excess acetone
with aromatic and a-branched aldehydes was found to proceed
in the presence of a catalytic amount of proline (typically 20–
30 mol%) in DMSO to provide the corresponding acetone aldols
with good yields and enantioselectivities. Primary a-amino acids,
too, have been screened as catalysts and have turned out to
efficiently catalyze the reaction of cycloalkanones2 as well as of
protected hydroxyacetone and dihydroxyacetone3 as the carbonyl
donors.
Several efforts have recently been devoted to the design of more
efficient catalysts for the direct asymmetric aldol reactions.1a,4
From a practical point of view there is a strong commitment
toward both optimizing catalyst activity (loading, selectivity, etc.)
and operational protocols (excess of donor, the solvent issue, etc.)
as well as designing recoverable and reusable catalysts, one of the
major goals of organocatalysis. In the last two years, some of the
most outstanding achievements in terms of catalytic efficiency have
been those involving aqueous biphasic conditions. In particular
we refer to reactions carried out under heterogeneous conditions,
wherein, however, all the reacting components, inclusive of the
catalyst, are present in the organic phase at the outset of the
reaction.
In the above context, since 2006, most of the best achievements
have been reported for catalysts consisting of chiral amines5
or amides6 deriving from L-proline, and for O-modified trans-
4-hydroxy-L-proline derivatives.7 The general strategy adopted
was to install hydrophobic substituents on the proline structure,
resulting in the abatement of the original hydrophilicity of the
reference amino acid.
Thus, the hydrophobic catalyst does not dissolve appreciably
in water, and forms with the donor–acceptor pair an organic
phase. Even though the catalytic cycle takes place in the water
saturated concentrated hydrophobic phase (or in the organic–
water boundary layer), the presence of the aqueous phase is
essential to ensure optimum results.8
A confirmation that formation of a such a biphasic system, with
all the reacting components exclusively confined in the organic
phase, is a necessary condition to get good results is demonstrated
by the fact that water miscible ketones afforded moderate yield and
stereoselectivity in water.5,7a This was further verified by Maya et al.
who reported exceptional stereochemical results using acetone as
a donor in an aqueous environment consisting of brine, necessary
to decrease the water solubility of acetone by salting out.6a
If maximizing catalyst hydrophobicity is the key to success in
the organocatalysed aldol reaction under liquid–liquid biphasic
aqueous conditions, this property, however, does not provide a
practical recycling procedure, since at the extraction stage catalyst
and products will be extracted into the same solvent.
The strategy we suggest to design a catalyst that joins efficiency
and recyclability under liquid–liquid biphasic aqueous conditions,
is to confer on it the correct amphiphilicity profile. That would
allow the catalyst to move from water, where it might be present
dissolved at the outset, to the organic phase consisting of the
donor–acceptor pair. Secondly, in the work-up stage, it would
allow the catalyst to move from the organic solvent used to
separate the aldol products back into water. Such a delicate
balance of solubility properties is much easier to address by using
the ionic tagging strategy in catalyst design.10 A catalytically active
molecular frame is tagged with a side chain containing a charged
group, e.g. an onium group. This approach allows us to tune the
partition coefficient of the catalyst in biphasic systems by a suitable
choice of ion pair structure.
Ionic liquid-supported catalysts of general structure 1 (Fig. 1),
where the charged tag is connected to the 4-OH group of trans-4-
hydroxy-L-proline, have been reported in recent literature to ensure
good catalytic and stereochemical performances in the asymmetric
cross-aldol reaction.
Miao and Chan first reported the use of 1a as an efficient
aldolization catalyst in DMSO or acetone as the solvent.11 We
demonstrated that catalytic performances of 1b are substantially
improved by the coulombic environment created by an ionic liquid
(IL) used as the solvent.12 Catalyst 1c was used in an analogous
way in ILs by Zhou and Wang.13 Finally, catalyst 1d was recently
reported to work under aqueous biphasic conditions allowing
an easy recycling of the catalyst.14 Even though long lipophilic
chains are installed on 1d, the outstanding role of the anion in
Dipartimento di Chimica “G. Ciamician”, Universita` di Bologna, via Selmi
2, Bologna, Italy. E-mail: marco.lombardo@unibo.it, claudio.trombini@
unibo.it; Fax: +39 051 2099558; Tel: +39 051 2099513
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR; chiral HPLC details. See DOI: 10.1039/b812607k
4224 | Org. Biomol. Chem., 2008, 6, 4224–4229
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
2 in our hands, we investigated whether the hydrolysis of 2 to
the trihydroxysilyl species 3 was followed by polycondensation
in a kind of self-directed assembly of particles,15 which, in
turn, could be candidates as catalysts for the asymmetric aldol
reaction. Complete hydrolysis occurred when 2 was subjected
to hydrogenolytic conditions in MeOH. The proline derivative
3 was perfectly soluble in water, and even in the presence of
trace amounts of HCl, no trace of aggregation into nanoparticles
was observed by dynamic light scattering measurements. When
3, in water, was tested as a catalyst in the aldol reaction of
cyclohexanone and p-nitrobenzaldehyde, no reaction occurred at
rt after 72 h.
Fig. 1 General structure of ion-tagged prolines 1.
determining the catalyst partitioning is witnessed. Indeed, the use
of BF4 as the counterion instead of lipophilic PF6 abated the
catalyst activity under aqueous heterogeneous conditions.
Since the lipophilicity/hydrophilicity profile of an ionic liquid
is strongly reshaped by passing from halides to the hydrophobic
bis(trifluoromethylsulfonyl)imide ion (Tf2N-), we first subjected
2 to a Cl-–Tf2N- metathesis reaction to obtain 4, which was
then exposed to Pd/C catalyzed hydrogenolysis conditions in
wet EtOAc (Scheme 2). Quantitative deprotection was again
accompanied by complete hydrolysis of the triethoxy moiety,
releasing 5 which was still soluble in water. Herein too, no evidence
of spontaneous polycondensation resulted from dynamic light
scattering measures.
-
-
Results and discussion
Installation of the (3-(3-trihydroxysilylpropyl)-imidazolium-1-yl)-
acetate tag on the 4-position of 4-hydroxy-L-proline
En route to structures like 1, we synthesized the intermediate 3
containing a trialkoxysilyl group on the R appendage, according
to the reaction sequence shown in Scheme 1.
Scheme 2 The synthesis of ionic-tagged proline 3.
The use of ionic-tagged proline 5 as a catalyst for the direct
asymmetric aldol reaction
With compound 5 in our hands, we checked it as a catalyst in the
benchmark reaction of cyclohexanone and p-nitrobenzaldehyde.
The experiment was conducted under neat conditions in the
absence of water. After stirring 5 equivalents of cyclohexanone
◦
and p-nitrobenzaldehyde (the limiting reagent) for 16 h at 28 C
in the presence of 10 mol% of 5, the aldol 6 was isolated in 80%
chemical yield, with an anti diastereoselectivity = 80 : 20, the anti-
aldol being produced in 85% ee. This preliminary result prompted
us to explore different reaction conditions in order to identify a
more efficient catalytic protocol. The reaction in the presence of
water was checked at first, according to the chemical evidence on
the sometimes conflicting role of water on the outcome of the
Scheme 1 The synthesis of ionic-tagged proline 3.
At the outset, the aim of this study was the preparation of hybrid
‘organic–inorganic’ mesoporous silicas using soft chemistry. With
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4224–4229 | 4225
©

View Article Online
aldol reaction.9,16 If, indeed, the commonly accepted mechanism
for the organocatalysed aldol reaction,1 as well as for the action
of class I aldolases,17 involves the intermediate formation of an
enamine, a few equivalents of water are necessary, too, to speed
up the catalytic cycle. On the other hand, a massive presence of
water is supposed to favor the hydrolysis of the enamine, unless the
reaction takes place in an organic compartment (a hydrophobic
pocket in the case of the enzyme) separated from the aqueous
phase.
When the amount of water was progressively increased, both
yield and stereochemical outcome improved, up to a top value
of 92% yield, accompanied by an excellent diastereoselectivity
(anti–syn = 96 : 4) and a remarkable enantioselectivity (anti-6
was produced in 99% ee) after stirring for 24 h at 28 ◦C using the
amount of water and the conditions shown in Scheme 3. Doubling
the amount of water did not produce any change both in terms of
chemical and stereochemical results.
3). The excellent anti–syn ratios displayed by cyclohexanone
(run 2) is not shared by cyclopentanone and cycloheptanone
(runs 1 and 3), the latter being the least reactive aldol donor.
Correspondingly, an outstanding enantioselectivity was recorded
both with cyclohexanone and cyclopentanone, cycloheptanone
(run 3) being the only exception.
Electron withdrawing groups favor the aldol reaction (runs 4–6)
while halobenzaldehydes (runs 7,8) and unsubstituted aldehydes
(runs 9,10) require a longer time to reach good yields. In 6
examples out of ten, enantioselectivities were ≥99%, and in all the
examples involving cyclohexanone, diastereomeric anti–syn ratios
were ≥95 : 5.
Unfortunately, the foregoing reaction protocol suffered for the
main limitation of being not applicable to aliphatic aldehydes.
To widen the scope of the cross-aldol reaction to aliphatic
aldehydes, i.e. isobutyraldehyde and cyclohexane carboxaldehyde
as acceptors, we started re-examining other reaction conditions.
Again, the amount of water was revealed to be a critical factor, as
shown by the results collected in Table 2.
Table 2 Direct aldol reaction of aliphatic aldehydes and cyclohexanone
with organocatalyst 5
Scheme 3 Conditions adopted for the aldol reaction protocol.
This preliminary result, achieved under liquid–liquid biphasic
conditions, meant that 5 possessed the optimum partitioning
coefficient to be extracted by cyclohexanone into the organic
layer of the water–cyclohexanone biphasic system.18 The reaction
was carried out under efficient stirring to ensure formation of
an emulsion in which the surface area between the two phases
was maximized, as well as the transport of 5 into the organic
phase. Conversely, using proline derivatives with hydrophobic
substituents, it is reported that efficient stirring is less significant,
owing to the complete insolubility of the catalyst in water.7a
An outstanding stability of the stereochemical performance
both in terms of dr and ee was also observed when catalyst
loading was varied. When the mol% of catalyst was decreased from
10% to 5%, 2.5% and 1%, it reflected only on reduced chemical
yields, which after 24 h passed from 92% to 80%, 65% and 30%,
respectively. We then explored the scope of the reaction using
different substrates and the results are summarized in Table 1.
Setting the reaction time at 24 h and using 4-nitrobenzaldehyde,
we first compared the reactivity of cycloalkanones (runs 1–
Run
R
H2O (mL)
6, Yield (%)a
anti–synb anti ee (%)c
1
2
3
4
i-Pr
0.8
0.8
0.012
0.012
6k, 9
6l, 7
6k, 58
6l, 50
>99 : 1
>99 : 1
>99 : 1
>99 : 1
99
99
99
99
c-C6H11
i-Pr
c-C6H11
a Refers to isolated yields. b Determined by 1H NMR of the products.
c Determined by chiral HPLC (see ESI†).
Recycling experiments
Thus, having exploited the partitioning properties of 5 in a
profitable reaction protocol, we addressed the second important
goal mentioned earlier, that is, the recyclability of the catalyst. The
complete insolubility of 5 in ether and its corresponding solubility
in water formed the basis of an efficient separation of 5 from the
product and of a simple catalyst recycling procedure.
Table 1 Asymmetric aldol reactions catalysed by 5
Run
Ar
n
t/h 6, Yield (%) anti–synb anti ee (%)c
The reaction work-up by a direct extraction with ether of the
reaction mixture was not efficient since part of the catalyst was
extracted in the cyclohexanone containing organic phase. We
modified the work-up procedure by preliminarily removing both
ketone and water under reduced pressure (~0.1 mmHg, rt). The
solid residue was eventually partitioned between water and ether.
During the elimination of the excess of ketone and water, all the
enamine present in solution was hydrolysed delivering a residue
which consisted of free 5 and the aldol product, only. Separation
of the product did occur very efficiently with no loss of catalyst
into the ether phase, while the catalyst remained in the aqueous
phase ready to be reused.
1
2
3
4
5
6
7
8
9
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
2-NO2-C6H4
4-CN-C6H4
C6F5
4-Br-C6H4
4-Cl-C6H4
2-Naphthyl
Ph
0
1
2
1
1
1
1
1
1
1
24
24
24
24
24
24
72
70
72
72
6a, 98
6b, 92
6c, 25
6d, 60
6e, 87
6f, 93
6g, 81
6h, 78
6i, 78
6j, 60
70 : 30
96 : 4
73 : 27
>99 : 1
96 : 4
99 : 1
96 : 4
96 : 4
95 : 5
95 : 5
97
99
82
>99
>99
>99
>99
>99
96
10
99
a Yields refer to isolated products. b Determined by 1H NMR of the
products. c Determined by chiral HPLC (see ESI).
4226 | Org. Biomol. Chem., 2008, 6, 4224–4229
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Table 3 Recycling experiments under the same conditions reported for
were monitored by TLC and GC-MS. Flash-chromatography was
carried out using Merck silica gel 60 (230–400 mesh particle size).
All reagents were commercially available and were used without
further purification, unless otherwise stated.
Table 1, run 2
Cycle
6a, Yield (%)a
anti–synb
anti ee (%)c
1
2
3
4
5
93
94
88
76
51
96 : 4
95 : 5
95 : 5
96 : 4
94 : 6
99
98
97
98
87
3-Iodopropyltriethoxy silane. A solution of 3-chloropropyl-
triethoxy silane (12.04 mL, 50 mmol) and NaI (7.49 g, 50 mmol)
in anhydrous acetone (40 mL) was stirred under reflux for 24 h.
The reaction was monitored using GC-MS. The solvent was then
evaporated under reduced pressure, the residue was filtered over
celite and washed with ether (15 mL). The ether was then removed
in vacuo and the crude residue was distilled to obtain the pure 3-
iodopropyltriethoxy silane (13.85 g, 83%). GC-MS: tR = 14.3 min;
m/z = 332. 1H NMR (200 MHz, CDCl3): 0.63–0.77 (m, 2 H), 1.19
(t, J = 7.0 Hz, 9 H), 1.75–2.00 (m, 2 H), 3.19 (t, J = 7.1 Hz, 2 H),
3.79 (q, J = 7.0 Hz, 6 H). 13C NMR (50 MHz, CDCl3): 10.5, 12.2,
18.2, 27.5, 58.3. Anal. Calcd for C9H21IO3Si (332.25): C, 32.53; H,
6.37. Found: C, 32.46; H, 6.35%.
a Refers to isolated yields. b Determined by 1H NMR of the products.
c Determined by chiral HPLC (see ESI†).
Indeed, the catalyst containing aqueous phase was directly
charged with the aldol reaction partners and the reaction was
run for a few cycles. Results of 5 cycles under the same conditions
reported in Table 1 run 2, are collected in Table 3.
Recovered yields in the first three runs were essentially stable,
and only in the fourth cycle a 20% drop in chemical yield was
recorded, while a decrease of the enantioselectivity by a factor
of 12% was observed only in the fifth cycle. A partial catalyst
epimerization in the long run can occur, likely as the consequence
of the formation of iminium ions between the proline group
and the aldehyde. It is indeed known that heating proline in the
presence of a catalytic amount of an aldehyde provides an efficient
racemization protocol.19
N-(3-Triethoxysilyl)propyl imidazole. To a suspension of NaH
(0.792 g, 33 mmol) in anhydrous THF (55 mL) at 0 ◦C was added
imidazole (2.25 g, 33 mmol) and it was allowed to stir for 30 min.
3-Iodopropyltriethoxy silane (9.97 g, 30 mmol) was then added to
◦
the reaction mixture at 0 C. The reaction was allowed to warm
to room temperature and stirred under reflux for a further 24 h.
The conversion was monitored using GC-MS. The reaction was
cooled to room temperature, filtered over celite and washed with
ether. The filtrate was concentrated in vacuo and the crude product
was purified by distillation under vacuum using a Kugel-Rohr
Conclusions
1
We have demonstrated that a water soluble organocatalyst can
be designed to function in a highly efficient and stereoselective
fashion in the asymmetric cross-aldol reaction under aqueous
biphasic conditions by a modulation of its partition coefficients in
different aqueous biphasic environments. The cationic frame of the
new proline derivative 5 contains three hydrophilic portions that
render it very soluble in water. On the other hand, coupling the
hydrophilic cation of 5 to the highly hydrophobic Tf2N- ion gives
rise to an optimized favourable partitioning of the new catalyst
5 not just during the reaction stage but also during the work-up.
Indeed, in the reaction stage, 5 is transported to the organic phase
of the biphasic ketone–water system where the aldol reaction takes
place in high yields and remarkable stereocontrol. In particular,
using cyclohexanone as a donor, anti–syn ratios were ≥95 : 5 and
ee’s were up to ≥99%. In the work-up stage, on the other hand,
aldol products and 5 were efficiently separated by partitioning
them between ether and water, 5 being soluble in water but not in
ether. This offers the opportunity to recycle 5, which was used for
4 runs without loss of its original stereochemical performances.
apparatus; 5.68 g, 70%. GC-MS: tR = 18.1 min; m/z = 272. H
NMR (200 MHz, CDCl3): 0.56 (dd, J = 9.0, 7.1 Hz, 2 H), 1.21
(t, J = 7.0 Hz, 9 H), 1.78–1.98 (m, 2 H), 3.80 (q, J = 7.0 Hz,
6 H), 3.93 (t, J = 7.0 Hz, 2 H), 6.91 (s, 1 H), 7.04 (s, 1 H), 7.47
(s, 1 H). 13C NMR (50 MHz, CDCl3): 7.2, 18.1, 24.7, 49.0, 58.2,
58.3, 118.6, 129.0, 137.0. Anal. Calcd for C12H24N2O3Si (272.42):
C, 52.91; H, 8.88; N, 10.28. Found: C, 53.08; H, 8.86; N, 10.27%.
N-Benzyloxycarbonyl-(2S,4R)-4-(2-chloroacetyl)proline benzyl
ester. To an ice-cold solution of N-benzyloxycarbonyl-(2S,4R)-
4-hydroxyproline benzyl ester (5.34 g, 15 mmol) and 2-chloroacetyl
chloride (1.88 g, 16.5 mmol) in CH2Cl2 (20 mL) was slowly added
pyridine (1.31 g, 16.5 mmol). The reaction mixture was allowed
to warm to room temperature and stirred for a further 12 h. The
precipitate was removed by filtration and the filtrate was washed
with water (20 mL), 10% aq. NaHCO3, then dilute HCl (2 M)
and finally water (20 mL). The solution was dried over Na2SO4,
concentrated under vacuum and the crude residue was purified
by silica-gel column chromatography (cyclohexane–ethyl acetate,
70 : 30) to give the title compound as a thick oil (5.13 g, 79%
yield). [a]2D0 = -42.0 (c 1.0, CHCl3); 1H-NMR (200 MHz, CDCl3;
2 conformational isomers): 2.16–2.37 (m, 1 H), 2.39–2.59 (m, 1 H),
3.66–3.93 (m, 2 H), 4.00–4.10 (m, 2 H), 4.43–4.66 (m, 1 H), 5.04
(d, J = 10.3 Hz, 2 H), 5.14–5.27 (m, 2 H), 5.38 (br. s., 1 H), 7.17–
7.47 (m, 10 H); 13C-NMR (75 MHz, CDCl3; 2 conformational
isomers): 35.4 and 36.4, 40.6, 51.9 and 52.4, 57.6 and 57.9, 67.1
and 67.2, 67.4, 73.7 and 74.4, 127.9, 128.1, 128.2, 128.3, 128.4,
128.5, 128.6, 135.1 and 135.3, 136.1 and 136.2, 154.1 and 154.6,
166.7 and 166.8, 171.5 and 171.8. Anal. Calcd for C22H22ClNO6
(431.87): C, 61.18; H, 5.13; N, 3.24. Found: C, 60.97; H, 5.11; N,
3.22%.
Experimental
General and materials
1H and 13C NMR spectra were recorded on Varian Inova 300
and Varian Gemini 200 spectrometers; chemical shifts (d) are
reported in ppm relative to TMS. Gas chromatographic analyses
were performed with an Agilent 6850 instrument coupled to an
Agilent 5975 quadrupole mass detector (50 ◦C, 2 min → 280 ◦C,
10 ◦C/min → 280 ◦C, 10 min). Chiral HPLC studies were carried
out on a Hewlett-Packard series 1090 instrument. Reactions
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4224–4229 | 4227
©

View Article Online
N-(3-Triethoxysilyl)propyl imidazolium chloride-tagged N-Cbz-
proline benzyl ester (2). To a solution of N-benzyloxycarbonyl-
(2S,4R)-4-(2-chloroacetyl)proline benzyl ester (5.94 g,
13.75 mmol) in CH3CN (10 mL) was added N-(3-
triethoxysilyl)propyl imidazole (3.97◦ g, 14.58 mmol) and
the reaction mixture was heated at 60 C for 12 h. The CH3CN
was then removed under reduced pressure. The crude product
was washed with anhydrous ether (5 mL ¥ 4) and vacuum dried
to obtain the quarternised compound 2 as a hygroscopic solid
(8.14 g, 84% yield). [a]2D0 = -11.2 (c 0.86, CHCl3); 1H-NMR
(300 MHz, CDCl3): 0.59 (t, J = 7.2 Hz, 2 H), 1.21 (td, J = 7.0,
2.2 Hz, 9 H), 1.98 (dq, J = 7.7, 7.5 Hz, 2 H), 2.14–2.32 (m, 1 H),
2.48–2.70 (m, 1 H), 3.70–3.90 (m, 7 H), 4.24 (t, J = 7.0 Hz, 2 H),
4.46–4.59 (m, 1 H), 5.01 (dd, J = 11.2, 1.7 Hz, 2 H), 5.09–5.20
(m, 2 H), 5.28–5.42 (m, 2 H), 5.53–5.75 (m, 1 H), 5.92 (d, J =
17.8 Hz, 1 H), 7.15–7.42 (m, 11 H), 7.59 (s, 1 H), 10.53 (s, 1 H);
13C-NMR (75 MHz, CDCl3; 2 conformational isomers): 6.1, 17.4,
23.3, 34.4 and 35.3, 49.2, 50.9 and 51.3, 56.6 and 57.1, 57.2, 57.6,
65.9, 66.2 and 66.3, 73.7 and 73.9, 120.4, 123.6, 126.7, 126.8,
127.0, 127.1, 127.3, 127.4, 127.5, 127.58, 127.60, 134.3, 134.5,
135.2, 135.3, 137.0, 153.1 and 153.6, 165.3, 170.8, 171.0. Anal.
Calcd for C34H46ClN3O9Si (704.28): C, 57.98; H, 6.58; N, 5.97.
Found: C, 57.78; H, 6.60; N, 5.94%.
N-(3-Trihydroxysilyl)propyl imidazolium trifluoro methanesulfo-
nimide-tagged proline (5). To a solution of 4 (4.75 g, 5 mmol) in
EtOAc (15 mL) was added palladium on charcoal (10%, 530 mg,
0.5 mmol). The mixture was stirred under hydrogen at room
temperature under atmospheric pressure for 7 h. The reaction
mixture was filtered over celite and washed with CH3CN (15 mL).
The filtrate was concentrated in vacuo to obtain the catalyst 5
as a pale brown low-melting solid (3.17 g, 99% yield). [a]D20
=
1
-11.4 (c 1.1, MeOH); H-NMR (200 MHz, CD3OD): 0.47–0.79
(m, 2 H), 1.89–2.16 (m, 2 H), 2.25–2.47 (m, 1 H), 2.51–2.71 (m,
1 H), 3.45–3.61 (m, 2 H), 4.12–4.39 (m, 3 H), 5.16–5.24 (m, 2 H),
5.46–5.64 (m, 1 H), 7.66 (s, 2 H), 9.00 (s, 1 H). 13C-NMR
(75 MHz, CD3OD): 25.3, 36.2, 39.4, 50.9, 53.9, 54.7, 61.3, 71.4,
119.2, 123.4, 125.5, 127.7, 138.7, 168.7, 174.5. Anal. Calcd for
C15H22F6N4O11S2Si (640.56): C, 28.13; H, 3.46; N, 8.75. Found: C,
28.04; H, 3.44; N, 8.78%.
Typical experimental procedure for the cross-aldol condensation.
Catalyst 5 (16 mg, 0.025 mmol) was stirred in water (0.8 mL) until a
clear solution was obtained. Cyclohexanone (0.259 mL, 2.5 mmol)
was then added and stirred for a further 20 min, whereupon the
reaction mixture was an emulsion. p-Nitrobenzaldehyde (75.5 mg,
0.5 mmol) was added to the reaction mixture and stirred at
room temperature for the appropriate time; the nature of the
reaction mixture remained an emulsion over the time period.
The cyclohexanone and water were then removed under reduced
pressure, water (0.8 mL) was added to the residue and it was
extracted with Et2O (3 mL ¥ 4). The combined organic extracts
were dried over Na2SO4, concentrated in vacuo and purified by
silica-gel column chromatography (cyclohexane–ethyl acetate, 7 :
3) to obtain the pure aldol adducts.
N-(3-Trihydroxysilyl)propyl imidazolium chloride-tagged proline
(3). To a solution of 2 (3.52 g, 5 mmol) in MeOH (15 mL)
was added palladium on charcoal (10%, 530 mg, 0.5 mmol). The
mixture was stirred under hydrogen at room temperature under
atmospheric pressure for 8 h. The reaction mixture was filtered
over celite and washed with CH3CN (15 mL). The filtrate was
concentrated in vacuo to obtain 3 as a pale brown very hygroscopic
solid (1.96 g, 99% yield). [a]2D0 = -10.3 (c 1.1, CH3OH); 1H-NMR
(200 MHz, CD3OD): 0.55–0.81 (m, 2 H), 1.93–2.16 (m, 2 H), 2.31–
2.49 (m, 1 H), 2.56–2.75 (m, 1 H), 3.35 (s, 2 H), 3.50–3.59 (m, 1 H),
3.62–3.70 (m, 1 H), 3.81–3.87 (m, 1 H), 4.22–4.47 (m, 1 H), 5.18–
5.39 (m, 2 H), 5.47–5.62 (m, 1 H), 7.74 (br. s., 1 H), 9.24 (br. s.,
1 H). 13C-NMR (50 MHz, CD3OD): 25.2, 30.1, 36.2, 51.8, 53.2,
60.9, 71.2, 77.1, 123.6, 125.5, 139.0, 167.8, 172.2. Anal. Calcd for
C13H22ClN3O7Si (395.87): C, 39.44; H, 5.60; N, 10.61. Found: C,
39.49; H, 5.65; N, 10.56%.
Typical experimental procedure for recycling studies. The re-
cycling studies were performed using the typical experimental
procedure for the cross-aldol condensation on a 1 mmol scale
of the aldehyde. After completion of the Et2O extraction, the
reaction flask was dried under vacuum (~0.1 mmHg, rt) for 1 h
and recharged with the starting substrates.
References
N-(3-Triethoxysilyl)propyl imidazolium trifluoromethane-sulfo-
nimide-tagged N-Cbz-proline benzyl ester (4). A solution of 2
(8 g, 11 mmol) and N-lithiotrifluoromethane-sulfonimide (3.32 g,
11.55 mmol) in CH2Cl2 (10 mL) was stirred at room temperature
for 5 h. The reaction mixture was then washed with H2O (3 mL)
and dried over Na2SO4. Concentration of the organic layer under
vacuum afforded 4 as a brown hygroscopic solid (10.3 g, 99% yield)
that was used without further purification for the debenzylation
step. [a]2D0 = -5.7 (c 0.58, CHCl3); 1H-NMR (200 MHz, CDCl3):
0.52–0.68 (m, 2 H), 1.12–1.36 (m, 9 H), 1.84–2.09 (m, 2 H), 2.15–
2.37 (m, 1 H), 2.41–2.65 (m, 1 H), 3.64–3.94 (m, 8 H), 4.06–4.32
(m, 2 H), 4.43–4.62 (m, 1 H), 4.92–5.26 (m, 6 H), 5.38 (br. s., 1 H),
7.15–7.48 (m, 12 H), 8.88 (s, 1 H); 13C-NMR (75 MHz, CDCl3;
2 conformational isomers): 6.2, 6.6, 17.88, 17.93, 23.9, 35.0, 35.8,
49.5, 50.3, 51.8, 57.8, 58.35, 66.8, 67.16, 67.23, 117.4, 121.6, 123.9,
127.3, 127.4, 127.7, 127.8, 127.9, 128.16, 128.22, 128.27, 128.32,
134.9, 135.7, 136.6, 154.1, 154.6, 165.4, 171.6, 171.7. Anal. Calcd
for C36H46F6N4O13S2Si (948.98): C, 45.56; H, 4.89; N, 5.90. Found:
C, 45.62; H, 4.87; N, 5.88%.
1 (a) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev.,
2007, 107, 5471; (b) B. List, Tetrahedron, 2002, 58, 5573; (c) B. List, P.
Pojarliev and C. Castello, Org. Lett., 2001, 3, 573; (d) B. List, Synlett,
2001, 1675; (e) W. Notz and B. List, J. Am. Chem. Soc., 2000, 122, 7386;
(f) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000,
122, 2395.
2 (a) M. Lombardo, S. Easwar, F. Pasi, C. Trombini and D. D. Dhavale,
Tetrahedron, 2008, 64, 9203; (b) A. Co´rdova, W. Zou, P. Dziedzic, I.
Ibrahem, E. Reyes and Y. Xu, Chem.–Eur. J., 2006, 12, 5383; (c) A.
Co´rdova, W. Zou, I. Ibrahem, E. Reyes, M. Engqvist and W.-W. Liao,
Chem. Commun., 2005, 3586.
3 (a) S. S. V. Ramasastry, H. Zhang, F. Tanaka and C. F. Barbas III, J. Am.
Chem. Soc., 2007, 129, 288; (b) S. S. V. Ramasastry, K. Albertshofer, N.
Utsumi, F. Tanaka and C. F. Barbas III, Angew. Chem., Int. Ed., 2007,
46, 5572.
4 (a) D. Enders and C. Grondal, Angew. Chem., Int. Ed., 2005, 44, 1210;
(b) J. Casas, M. Engqvist, I. Ibrahem, B. Kaynak and A. Co´rdova,
Angew. Chem., Int. Ed., 2005, 44, 1343; (c) W. Notz, F. Tanaka and
C. F. Barbas III, Acc. Chem. Res., 2004, 37, 580.
5 N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and C. F.
Barbas III, J. Am. Chem. Soc., 2006, 128, 734.
6 (a) V. Maya, M. Raj and V. K. Singh, Org. Lett., 2007, 9, 2593; (b) C.
Wang, Y. Jiang, X.-X. Zhang, Y. Huang, B.-G. Li and G. L. Zhang,
Tetrahedron Lett., 2007, 48, 4281; (c) Y. Wu, Y. Zhang, M. Yu, G. Zhao
4228 | Org. Biomol. Chem., 2008, 6, 4224–4229
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
and S. Wang, Org. Lett., 2006, 8, 4417; (d) Y.-Q. Fu, Z.-C. Li, L.-N.
Ding, J.-C. Tao, S.-H. Zhang and M.-S. Tang, Tetrahedron: Asymmetry,
2006, 17, 3351; (e) S. Guizzetti, M. Benaglia, L. Raimondi and G.
Celentano, Org. Lett., 2007, 9, 1247.
7 (a) S. Aratake, T. Itoh, T. Okano, N. Nagae, T. Sumiya, M. Shoji and Y.
Hayashi, Chem.–Eur. J., 2007, 13, 10246; (b) Y. Hayashi, T. Sumiya, J.
Takahashi, H. Gotoh, T. Urushima and M. Shoji, Angew. Chem., Int.
Ed., 2006, 45, 958; (c) Y. Hayashi, S. Aratake, T. Okano, J. Takahashi,
T. Sumiya and M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 5527; (d) J.
Huang, X. Zhang and D. W. Armstrong, Angew. Chem., Int. Ed., 2007,
46, 9073.
8 Neat reactions in the absence of an aqueous phase have been shown to
furnish much poorer results; i.e. see ref. 5 and 7a,b.
9 Y. Jung and R. A. Marcus, J. Am. Chem. Soc., 2007, 129, 5492.
10 W. Miao and T. H. Chan, Acc. Chem. Res., 2006, 39, 897.
11 W. Miao and T. H. Chan, Adv. Synth. Catal., 2006, 348, 1711.
12 M. Lombardo, F. Pasi, S. Easwar and C. Trombini, Adv. Synth. Catal.,
2007, 349, 2061.
16 (a) A. Co´rdova, W. I. Ibrahem, E. Reyes, M. Engqvist and W.-W. Liao,
Chem. Commun., 2005, 3586; (b) P. Dziedzic, W. Zou, J. Hafren and
A. Co´rdova, Org. Biomol. Chem., 2006, 4, 38; (c) P. M. Pihko, K. M.
Laurikainen, A. Usano, A. I. Nyberg and J. A. Kaavi, Tetrahedron,
2006, 62, 317; (d) D. Font, C. Jimeno and M. A. Perica`s, Org. Lett.,
2006, 8, 4653; (e) Y. Wu, Y. Zhang, M. Yu, G. Zhao and S. Wang, Org.
Lett., 2006, 8, 4417; (f) W.-P. Huang, J.-R. Chen, X.-Y. Li, Y.-J. Cao and
W. - J. X i a o , Can. J. Chem., 2007, 85, 208; (g) X. Wu, Z. Jiang, H.-M.
Shen and Y. Lu, Adv. Synth. Catal., 2007, 349, 812; (h) L. Zu, H. Xie,
H. Li, J. Wang and W. Wang, Org. Lett., 2008, 10, 1211; (i) D. Font,
S. Sayalero, A. Bastero, C. Jimeno and M. A. Perica`s, Org. Lett., 2008,
10, 337.
17 S. W. B. Fullerton, J. S. Griffiths, A. B. Merkel, M. Cheriyan, N. J.
Wymer, M. J. Hutchins, C. A. Fierke, E. J. Toone and J. H. Naismith,
Bioorg. Med. Chem., 2006, 14, 3002.
18 To confirm this mechanistic picture, we reacted acetone and p-
nitrobenzaldehyde. After 24 h, 30% of aldol was isolated in a perfect
racemic composition. This is due, in our opinion, to the solubility
of acetone in water, leading the reaction to proceed essentially in the
aqueous phase.
13 L. Zhou and L. Wang, Chem. Lett., 2007, 36, 628.
14 D. E. Siyutkin, A. S. Kucherenko, M. I. Struchkova and S. G. Zlotin,
Tetrahedron Lett., 2008, 49, 1212.
15 (a) A. Shimojima, Z. Liu, T. Ohsuna, O. Terasaki and K. Kuroda,
J. Am. Chem. Soc., 2005, 127, 14108; (b) B. Boury and R. J. P. Corriu,
Chem. Commun., 2002, 795.
19 (a) S. Yamada, C. Hongo, R. Yoshioka and I. Chibata, J. Org. Chem.,
1983, 48, 843; (b) R. Grigg and H. Q. N. Gunaratne, Tetrahedron Lett.,
1983, 24, 4457; (c) T. Shiraiwa, K. Shinjo and H. Kurokawa, Bull.
Chem. Soc. Jpn., 1991, 64, 3251.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4224–4229 | 4229
©