Polymer-supported catalysts: enantioselective hydrogenation and hydrogen transfer reduction.

Article abstract of DOI:10.1016/S0960-894X(02)00258-5

Different types of heterogenized catalysts were involved in asymmetric reactions. Hydrogen transfer reduction was performed with amino alcohols derived from poly((S)-(GMA-co-EGDMA or DVB)) and hydrogenation with BINAP grafted onto PEG or copolymerized with isocyanates as ligands. Attempts of catalysts recycling are reported.

Full text of DOI:10.1016/S0960-894X(02)00258-5

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1841–1844
Polymer-Supported Catalysts: Enantioselective Hydrogenation
and Hydrogen Transfer Reduction
Christine Saluzzo, Thierry Lamouille, Damien Herault and Marc Lemaire*
´
Laboratoire de Catalyse et Synth e` se Organique, UMR 5622, Universite´ Claude Bernard Lyon 1, CPE,
4
3 Bd. du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Received 20 November 2001; accepted 1 February 2002
Abstract—Different types of heterogenized catalysts were involved in asymmetric reactions. Hydrogen transfer reduction was per-
formed with amino alcohols derived from poly((S)-(GMA-co-EGDMA or DVB)) and hydrogenation with BINAP grafted onto
PEG or copolymerized with isocyanates as ligands. Attempts of catalysts recycling are reported. # 2002 Elsevier Science Ltd. All
rights reserved.
For incorporation into pharmaceuticals, agrochemicals,
flavours and fragrances, the importance of enantio-
merically pure compounds is ever increasing. Thus, the
development of chiral technologies, based on the areas
of asymmetric synthesis, biotransformation, and reso-
lution that are applicable to industrial processes has
As a part of our research program in asymmetric cata-
lysis, we were interested in the development of new
asymmetric reusable polymer-supported catalysts. We
herein report asymmetric heterogeneous reduction of a
C¼O bond by hydrogen transfer or molecular hydro-
gen. Different kinds of polymers were involved in these
reactions. Hydrogen transfer reduction was performed
with amino-alcohol derivatives of enantiopure poly((S)-
glycidyl methacrylate-co-ethyleneglycol dimethacrylate)
(poly(GMA-co-EGDMA)) and poly((S)-glycidyl meth-
acrylate-co-divinylbenzene) (poly(GMA-co-DVB)) for
solid–liquid catalysis. Finally, hydrogenation with
molecular hydrogen was employed both in solid–liquid
and in liquid–liquid biphasic catalyses. The first one was
performed with BINAP grafted onto a polyethylene
glycol and the second one with polyureas containing the
BINAP structure.
1
become essential. Catalytic asymmetric synthesis often
has significant economical advantages over stoichio-
metric diastereoselective synthesis in the production of
enantiomerically pure compounds on an industrial
scale. However, in the use of an homogeneous catalysis,
a problem of practical importance is encountered,
namely that the separation of the catalyst from the
reaction products becomes difficult and usually requires
special treatment which destroys the catalyst, prohibit-
ing its recycling. One way to solve this problem would
be to employ a heterogeneous catalysis, particularly a
polymer supported homogeneous catalysis. This method
consists in fixing the catalyst to an insoluble solid sup-
port in a way that retains the advantages observed in
solution. Thus, homogeneous catalysts have been
Amino alcohols are known to be ligands for asymmetric
homogeneous and heterogeneous catalysis for C–C, C–O,
7
and C–H bond formations. This prompted us to use
2ꢀ5
attached to a variety of supports, in order to perform
the separation of the catalyst from the reaction mixture
by filtration, precipitation or extraction. However, the
choice of the support is crucial. The active sites must be
amino alcohol derivatives of enantiopure poly((S)-
GMA-co-EGDMA) and poly((S)-GMA-co-DVB) as
ligands for catalytic hydrogen transfer reactions. This
reaction presents the advantage over the hydrogenation
of avoiding the use of pressurized hydrogen, which
requires special equipment, but, on the other hand, it is
limited to substrates which are not base sensitive.
6
at the proper location and for organic polymers, a large
swelling with the reaction solvent is generally required.
We have synthesized poly((S)-GMA-co-EGDMA) (1)8
and poly((S)-GMA-co-DVB) (3) two precursor polymers.
*
1
Corresponding author. Tel.: +33-4-72-43-14-07; fax: +33-4-72-43-
4-08; e-mail: marc.lemaire@univ-lyon1.fr
0
960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00258-5

1842
C. Saluzzo et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1841–1844
Scheme 1.
An attempt to recycle, by filtration, the ruthenium
complex 2 led to a marked decrease in activity from 94
to 27% and lowered selectivity from 70 to 54%.
Scheme 2.
On the other hand, reduction with molecular hydrogen
presents the advantage over the hydrogen transfer
reduction to use neutral conditions which are required
for acid- or base-sensitive substrates. Of the many cata-
lysts developed for transition metal-catalyzed asym-
metric hydrogenations, the Ru–BINAP complexes have
become the most extensively applied, both in aca-
demia and industry, since they promote highly
enantioselective transformations over a wide range of
substrates with high substrate to catalyst ratios. Until
recently, few examples of polymer-supported BINAP
catalysts have been reported in the literature.
They were both formed by radical suspension poly-
8
8
merisation of enantiopure (S)-GMA (30 wt%) with
EGDMA or DVB, in the presence of AIBN, with a
mixture of cyclohexanol/dodecanol (91/9 wt/wt) and
1
0
11
2
(
% of aqueous polyvinylpyrrolidone (PVP) as stabilizer
Scheme 1). A 500 mL glass reactor equipped with a
stirring anchor runing at 400 rpm was used. Chiral
beads of 1 and 3 were isolated by sifting, with particle
size of about 106–300 mm (granulometric analysis).
They present, respectively, a specific surface area of 82
For solid/liquid catalysis, Bayston12 reported the hetero-
2
and 275 m /g (BET analysis), with, for both of them,
2
genization of BINAP by anchoring
a
mono-
.11 mmol/g of epoxyde function (elemental analysis).
functionalized derivative on a polystyrene resin via an
amide bond. For the Ru-catalyzed hydrogenation of b-
ketosters and functionalized olefins, it afforded high
enantioselectivities (70–100%) and activities (70–100%
yield) with low substrate/catalyst ratio (S/Cꢂ200).
Thus, the specific surface area greatly depended on the
nature of the crosslinker. The subsequent epoxide ring
opening with benzylamine, according to the procedure
9
of Sherrington, led to polyamino alcohols 2 and 4
(
1
3
Scheme 1).
More recently, Pu prepared the poly-(BINAP), by
copolymerization of a BINAP derivative with 1,4-
dibromo-2,5-dialkylbenzene. Complexed with rhodium,
it gives >95% conversion and enantioselectivities from
40 to 75% for the reduction of dehydroamino acid
derivatives (S/C=50). The reduction of methylaryl-
ketone was performed in the presence of (R,R)-diphenyl-
ethylene diamine (DPEDA) leading to 90% ee and
conversions up to 99%. Chan has recently prepared
Polymers 2 and 4 were involved in hydrogen transfer
reduction of acetophenone. This reduction was per-
formed at 80 C, in the presence of [RuCl ( p-cymene)]
2
as precursor and isopropanol as hydrogen source. The
reaction was carried out with a ratio acetophenone/Ru/
amino alcohol polymer unit/t-BuOK of 20/1/4/5
ꢁ
2
(
Scheme 2 ). The results are summarized in Table 1.
1
4
soluble chiral polyester and dendrimer BINAP deri-
1
5
The best conversion and enantioselectivity were
obtained with amino alcohol 2 (run 1), which was
derived from 1 (crosslinker: EGDMA). Ru-complex 4
vatives as Ru-ligand for the hydrogenation of acrylic
derivatives. In the case of the supported Ru-polyester
catalyst, 65–100% conversion and 88–95% ee with a
ratio S/C of 200 were found. For the Ru-dendrimer
catalyst, with S/C of 125, total conversion and similar ee
were observed.
(
crosslinker: DVB) was less efficient, only 41% conver-
sion and 37% ee were observed (run 2), although its
specific surface area is higher than 2, showing that the
nature of the crosslinking agent is crucial.
In order to heterogenize BINAP, we synthesized diam-
1
6
BINAP. Its subsequent polymerization with di[4-iso-
cyanatophenyl]methane and diisocyanatotoluene affor-
ded polyureas 5 (degree of polymerization (DP) of 15,
average molecular weight (M) of about 14000 g/mol)
and 6 (DP: 10, Mꢂ12,000 g/mol), respectively, which
Table 1. Ruthenium catalysed transfer reduction of acetophenone
Polyamino alcohol functionalizationa
Run
Catalytic reaction
Ratio (%)
mmol/g
Conv (%)b Ee (%)b
94c
41
70c
37
present pseudo-C symmetry (Scheme 3).
1
2
2
4
69
61
1.20
1.04
2
d
d
These polyureas, soluble in aprotic solvents (DMF and
DMSO), were used as ruthenium ligands for asymmetric
hydrogenation of methylacetoacetate, in methanol
(Scheme 4). The active cationic ruthenium complex
involved in this reduction was prepared in methanol
a
Determined by elemental analysis.
Determined by GC on a Supelco b-dex 225 (30 mꢃ0.25 mm). Reac-
b
tion time:
c
3
d
h.
0 h.
4

C. Saluzzo et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1841–1844
1843
Scheme 3.
onto a water soluble polymer such as polyacrylic acid
sodium salt or PEG. Only few examples of water-soluble
1
9
systems derived from BINAP have been reported.
Scheme 4.
We synthesized the water-soluble PEG derivative of
diam-BINAP (7) (Scheme 5) (number of PEG units:
1
10–113, M=5000 g/mol) according to the Veronese
2
0
procedure. A mixture of mono- and disubstituted
PEG diam-BINAP derivatives (mono/di: 70/30) was
formed as shown by MALDI-TOF analysis.
Table 2. Hydrogenation of methylacetoacetate with Ru-complexes of
5, 6 and BINAP
a
a
Run
L*
Use
Conv. %
Ee %
We first involved the reduction of the C¼C bond of
itaconic acid under homogeneous conditions (Scheme 6)
using a water ruthenium polymer-supported catalyst
1
2
3
4
5
6
7
5
5
6
6
6
6
1
2
1
2
3
4
100
53
99
99
99
99
99
99
>99
100
100
100
100
100
(RuCl -7) derived from BINAP (prepared in DMF from
2
the [RuCl (benzene)] precursor according to the pro-
2 2
2
1
cedure of Noyori). After 16 h, 91% of conversion with
9% ee were observed. This catalytic complex is less
b
BINAP
1
1
a
efficient than the corresponding BINAP one, in meth-
anol (homogeneous conditions), which led to total con-
version and 88% ee.
Determined by chiral GC analysis on Lipodex A (25 mꢃ0.25 mm)
column.
Homogeneous conditions.
b
from the [RuCl (benzene)] , according to the Noyori’s
2
We then tested biphasic substrate/water reduction of
C¼O bond. The hydrogenation of acetophenone was
2
1
7
method. The results are summarized in Table 2. For
the first use (runs 1 and 3), both polyureas gave similar
activities and enantioselectivities. However, Ru-complex
performed using (RuCl -7) in the presence of (S,S)-
2
DPEDA. Compared to the similar BINAP complex
which gave, in homogeneous conditions (i-PrOH as
6
gave better efficiency than Ru-complex 5 upon recy-
cling by simple filtration (runs 2, 4–6). This difference
could be explained by the rigidity of the active site
which is crucial for the selectivity and the stability of the
solvent), total conversion with 85% ee, (RuCl -7)–
2
DPEDA led to excellent conversion (99%) with
encouraging ee (21%) (Scheme 7). It is noteworthy that
DPEDA has a synergetic effect and permit the reduction
1
8
catalytic system, as notified by Pu.
2
2
of various aromatic ketones.
Another way for recycling catalysts consists of using
biphasic catalytic systems, particularly water-organic
solvents. There is an increasing interest in asymmetric
The reduction of ethyl acetoacetate in water (Scheme 4)
with (RuCl -7) affords, after careful extraction of the
water-soluble product with pentane, 100% of con-
version and 75% ee but, after recycling, only 20% con-
version and 56% ee were obtained. The former ee value
was less important and the conversion was identical to
2
1
9
hydrogenation using water-soluble catalysts.
This
water solubilization is mainly due to the introduction of
either a sodium sulfonate, a quaternary ammonium
function into their backbone or by grafting the ligands
Scheme 5.

1844
C. Saluzzo et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1841–1844
2. Vankelecom, I. F. J.; Jacobs, P. A. In Chiral Catalyst
Immobilization and Recycling; De Vos, D. E., Vankelecom, I.
F. J., Jacobs, P., Eds.; Wiley-VCH: Weinheim, 2000; pp 20–
4
3
2.
. Hodge, P. Chem. Soc. Rev. 1997, 26, 417.
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4. Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis
1
5
Recycling; De Vos, D. E., Vankelecom, I. F. J., Jacobs, P.,
Eds.; Wiley-VCH: Weinheim, 2000; pp 43–80.
997, 11, 1217.
. Bergbreiter, D. E. In Chiral Catalyst Immobilization and
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. Rolland, A.; Herault, D.; Touchard, F.; Saluzzo, C.;
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8
´
8
9
1
1
2
1
11.
that obtained in the homogeneous system using (RuCl2–
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. Lindsay, D.; Sherrington, D. C. React. Polym. 1985, 3, 327.
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01.
We have shown that polymer-supported ligands such as
amino alcohol resins and polymers derived from
BINAP were able to reduce C¼C or C¼O bonds in
biphasic catalytic conditions. Moreover, the hetero-
geneization of BINAP into polyurea was successful and
allowed the efficient asymmetric hydrogenation of car-
bonyl compounds.
2. Bayston, D. J.; Fraser, J. L.; Ashton, M. R.; Baxter, A. D.;
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1
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1
From the synthetic point of view, in most cases, the use
of these Ru-based ligands led to high conversions and in
some cases good enantioselectivities. On the other hand,
they offer easy separation of the catalyst from the reac-
tion mixture and their reuse is, in some cases, effective
without any loss either of conversion or enantio-
selectivity.
1
1
H. J. Chem. Soc., Chem. Commun. 1989, 5, 1208.
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