Homogeneous asymmetric transfer hydrogenation of ketones using a ruthenium catalyst anchored on chitosan: Natural chirality at work

Article abstract of DOI:10.1039/c2nj40175d

A pivaloyl functionalized chitosan biopolymer was used as a polyligand for the [Ru(p-cymene)Cl₂] moiety. The functionalized biopolymer containing a metal to saccharide ratio of 0.33 was used as a catalyst for the asymmetric transfer hydrogenation of ketones. The reactions gave yields up to 80% and enantiomeric excesses up to 72%, with the intrinsic chirality of chitosan being the only source of enantioselection.

Full text of DOI:10.1039/c2nj40175d

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LETTER
Homogeneous asymmetric transfer hydrogenation of ketones using a
ruthenium catalyst anchored on chitosan: natural chirality at workw
c
b
Mathieu Babin,ab Roxanne Clement, Jonathan Gagnon* and
´ ´
Frederic-Georges Fontaine*
´
a
Received (in Gainesville, FL, USA) 6th March 2012, Accepted 29th May 2012
DOI: 10.1039/c2nj40175d
A pivaloyl functionalized chitosan biopolymer was used as a
polyligand for the [Ru(p-cymene)Cl2] moiety. The functionalized
biopolymer containing a metal to saccharide ratio of 0.33 was
used as a catalyst for the asymmetric transfer hydrogenation of
ketones. The reactions gave yields up to 80% and enantiomeric
excesses up to 72%, with the intrinsic chirality of chitosan being
the only source of enantioselection.
abundant biopolymer on earth after cellulose. Chitosan is
biodegradable, non-toxic, biocompatible, and is also known
to have good metal binding ability through a primary amine
moiety.9 However, the solubility of chitosan is nearly restricted to
acidified water, because of a large network of intermolecular
hydrogen bonding that prevents the free movement of the poly-
meric chains.9 Fortunately, modifications on pristine chitosan help
to increase its solubility in organic solvents and can be used more
readily as a polyligand.10 We wish to report the grafting of a Ru(II)
organometallic moiety onto soluble 6-O-pivaloyl functionalized
chitosan. This species is one of the first examples of a soluble
biopolymer acting as an efficient catalyst for the asymmetric
reduction of ketones, demonstrating the possibility of using the
intrinsic chirality of polysaccharides as a soluble polymeric support.
High purity and high molecular weight pristine chitosan
(Mw = 567 kDa) was first functionalized by the addition of
the N-phthalimide group on the primary amine,11 followed by
the esterification of the 6-O-position using pivaloyl chloride to
generate 1, and the hydrazonolysis of the phthalamide to
generate back the primary amine (2) (Scheme 1).10b The
addition of [Ru(p-cymene)Cl2]2 to the chitosan support in a
methanol solution, followed by purification using ultrafiltration
to remove all uncoordinated metal species, generates a pale
orange solid (2–Ru) (Scheme 2). Energy dispersive X-ray spectro-
scopy confirmed that the metal complex was present on the
polymer in a metal to saccharide unit ratio of 0.33 (based on
the Ru/O ratio), with no loss of chlorine, as observed by the
Ru/Cl ratio of 0.47. Compared to most chitosan derivatives,
the low hydrophobicity of the pivaloyl groups allows 2–Ru
to be soluble in methanol, allowing for its spectroscopic
characterization in solution. A 13C NMR spectrum of 2–Ru
indicates that the Ru(p-cymene)Cl2 species is present, but the
aromatic resonances of the para-cymene (d = 101.1, 96.4, 79.0
The efficiency of BINAP ruthenium catalysts for the asymmetric
hydrogenation of unsaturated substrates is remarkable and is
amongst the most important tools for the introduction of
chirality in fine chemicals.1 However, the toxicity of transition
metals and the high cost of both the ruthenium and the chiral
ligands are limiting factors in the industrial scale-up of transition
metal catalysts for pharmaceutical applications. Several avenues
have been explored in order to improve the environmental
balance of these processes, such as by the use of less toxic metals,
notably iron,2 or by grafting the catalysts onto solid supports to
facilitate the purification process and to favour its reusability.3
Polysaccharides are perfect candidates for the anchoring of
catalysts for large scale applications. Not only are they one of
the main components of biomass, but they are also cheap to
produce and environmentally benign.4 In addition, they are one of
the most abundant sources of natural chirality. Although simple
sugars have been used as reagents5 or ligands6 for many enantio-
selective syntheses, the use of polysaccharides in asymmetric
synthesis is scarce7 and is mainly restricted as a chromatographic
support.8 Chitosan is a homopolymer composed of chiral
2-amino-2-deoxy-D-glucopyranosyl units that is obtained after
the deacetylation in alkali media of chitin, the second most
a
´
Departement de chimie and Centre de Recherche sur les proprietes
des interfaces et de la catalyse (CERPIC), Universite Laval,
´ ´
´
´
´
´
1045 Avenue de la Medecine, Cite Universitaire, Quebec, QC,
Canada G1V 0A6. E-mail: frederic.fontaine@chm.ulaval.ca;
Fax: +1 418 6565140
b
´
´
´
´
`
Departement de biologie, chimie et geographie, Universite du Quebec a
Rimouski 300, alle´e des Ursulines, Rimouski, QC, Canada G5L 3A1.
E-mail: jonathan_gagnon@uqar.qc.ca; Fax: +1 418 7241849
c Centre for Catalysis Research and Innovation, University of Ottawa 30,
Marie Curie, Ottawa, ON, Canada K1N 6N5
w Electronic supplementary information (ESI) available: Spectro-
scopic details for 2 and 2 and high throughput details. See DOI:
10.1039/c2nj40175d
Scheme 1 Synthesis of polyligand 2; (a) tBuC(O)Cl, pyridine, 75 1C,
39 h; (b) H2NNH2, CH3CH2OH : H2O (80 : 20), reflux, 5 h.10b
c
1548 New J. Chem., 2012, 36, 1548–1551
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loading were used with 50 equivalents of sodium isopropoxide
as the base. At low temperature (3 1C) in air for 24 hours, the
desired secondary alcohol was observed in 12% yield (run 2).
Chiral GC-MS confirmed that the S stereoisomer was the major
one in 72% enantiomeric excess based on the comparison with
commercial standards. Running the catalytic experiments under
nitrogen rather than air proved to be the most important factor
to obtain good yields of the desired secondary alcohol. Indeed,
running the catalytic experiment under anaerobic conditions for
24 hours at 25 1C yielded 62% of the desired product with an ee
of 70% (run 3). Increasing the reaction time to 48 hours
increased the yield to 71% with little effect on the ee (run 4),
while increasing the temperature to 65 1C (run 5) also increased
the yield (73%) but significantly reduced the enantiomeric
excess (66%). A high throughput approach was used to better
understand the effect of the base on this reaction (runs 6 to 16
and ESIw). As observed in run 6, more than one equivalent of
the base is needed in order for the reaction to occur, but with a
large excess of the base the yields and the ees both drop
significantly (runs 7–10). The catalyst loading does not seem
to affect greatly the number of turnovers, since it only increases
from 101 to 175 when the number of equivalents of the
substrate increases by 4-fold (runs 7 and 11–12). Modifying
the base to iPrOLi (run 13), MeONa (run 14), and EtONa
(run 15) decreased the yield around 70% while keeping the ee
constant. With tBuONa the yield remained at 78% (run 16).
The substrate scope was also studied, as displayed in
Table 2. Increasing the size of the aliphatic chain of the ketone
by changing the methyl to ethyl and iso-propyl groups gave
lower yields and lower ee as the size of the alkyl group
increased (runs 17–19). However, having a tert-butyl moiety
on the ketone allowed an important increase in enantiomeric
excess (78%). Substrates with electron withdrawing 4-fluoro-
phenyl- and electron donating 4-methoxyphenylmethylketone gave
both lower enantiomeric excesses and yields than acetophenone,
which suggest that the electrophilicity of the carbonyl moiety is not
the most important factor in this reaction. Whereas 3-methyl-2-
butanone yielded no stereospecification, the 3,3-dimethyl-2-
butanone gave some stereoselectivity (30% ee), albeit in low yield
(7%). Finally, the non-prochiral substrates 3-pentanone, cyclo-
hexanone and benzophenone gave the corresponding alcohols in
20, 26, and 55% yield.1c
Scheme 2 Synthesis of supported catalyst 2–Ru. L can either be a –Cl
or the amine from another glucosamine unit.
and 78.3) are as broad as the polymer backbone resonances
and more shielded compared to those of the metallic precursor
(d = 106.6, 103.5, 86.4 and 83.7) and are very close to those
observed for species Ru(p-cymene)Cl2(H2NCH2CN) (d =
103.6, 95.7, 82.0 and 80.2),12 which suggests coordination of the
metal center to the amine moiety of the polysaccharide (see ESIw).
It cannot be precluded that the active catalyst consists of a species
of general formula [Ru(p-cymene)Cl(H2NR)2]Cl (where H2NR
corresponds to one glucosamine unit). Indeed, the Ru loading
below 50%, the excellent activity of [(R)-RuCl((1S,2S)-N-
(SO2CF3)NCH(C6H5)CH(C6H5)NH2)(Z6-benzene)] as catalyst
for the asymmetric transfer hydrogenation of ketones,13 and the
inactivity of model compound Ru(p-cymene)(NH2C6H11)Cl2
(vide infra) support this hypothesis. However, the diastereotopic
methyl groups of the i-Pr of the para-cymene moiety are quite
narrow, suggesting the presence of a homogeneous coordination
environment.
Ruthenium para-cymene derivatives in the presence of chiral
amines have been shown to be excellent catalysts for the
asymmetric transfer hydrogenation (ATH) of ketones.14 Similarly,
the ATH of acetophenone was carried out in a methanol :
isopropanol solution (9 : 1) in order to investigate the catalytic
activity of anchored catalyst 2–Ru (Table 1). In the initial run,
66 equivalents of the test substrate relative to the ruthenium
Table 1 Asymmetric transfer hydrogenation of acetophenone using 2–Ru
Run
Base (equiv.)
Subs. (equiv.)
Yield (%)
ee (%)
1a
2a,b
3
None
66
66
66
66
1
28
72
70
72
66
—
68
65
63
62
67
67
67
67
67
68
iPrONa (50)
iPrONa (50)
iPrONa (50)
iPrONa (50)
iPrONa (1)
iPrONa (8)
iPrONa (25)
iPrONa (50)
iPrONa (100)
iPrONa (8)
iPrONa (8)
iPrOLi (8)
12
62
71
73
0
81
69
70
61
54
35
69
71
69
78
In order to have a more detailed understanding of the
mechanism of this reaction, few additional studies were carried
out. Both the hydrogenation of acetophenone in the presence
of 2 and with complex Ru(p-cymene)(NH2C6H11)Cl2 (3-Ru), a
homogeneous model of 2–Ru having a similar bonding mode,
did not yield any product. The addition of R-phenylethanol to
2–Ru under the typical catalytic conditions with 1 equivalent
of acetone afforded after 24 hours 32% of acetophenone and
3% of S-phenylethanol, suggesting that the process is reversible
and thermodynamically driven. Furthermore, the reduction of
benzophenone precludes the formation of an enolate ion during
catalysis, which would suggest that 2–Ru acts as a typical inner-
sphere system,15 although other routes cannot be eliminated
without further kinetic studies. These studies are however
limited by the degradation and precipitation of 2–Ru under
basic conditions, presumably by cleavage of the ester group,
which also limits the recycling of the catalyst.
4c
5d
6
66
125
125
125
125
125
250
500
125
125
125
125
7
8
9
10
11
12
13
14
15
16
MeONa (8)
EtONa (8)
tBuONa (8)
Reactions were run in a 9 : 1 methanol to isopropanol ratio at 25 1C
under N2 for 24 hours unless stated otherwise. The yields and ees were
determined by GC-MS (runs 1–5) or GC-FID/B-PM (runs 6–16)
a
b
on one run with anisole as internal standard. Run in air. 3 1C.
c
d
48 hours. 65 1C.
c
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Table 2 Hydrogenation of functionalized ketones
(determined by gel permeation chromatography) was purchased
from Marinard Biotech Inc. (Gaspe, Canada). Chitosan was
´
Run
Substrate
Yield (%)
ee (%)
70
mechanically ground down to 0.6 mm before utilization.
Coordination procedures were performed using Schlenck
techniques and solvents used were freshly distilled and
deoxygenated. Synthesis of poly[b-(1-4)-2-deoxy-2-phthalimido-
6-O-pivaloyl-D-glucopyranose]-N-phthaloyl chitosan was per-
formed following the literature.11 The synthesis of 1 and 2 has
been recently reported.10b
17
62
18
19
20
45
10
30
50
28
78
Ultrafiltration was realized with regenerated cellulose filtra-
tion membranes (Amicon YM) possessing a cut-off of 30 000
NMWL in a stirred cell bought from Millipore. 13C solid-state
NMR spectra were recorded on a Bruker DSX300 NMR
spectrometer at 75 MHz with a 4 mm CP/MAS probe, a
contact time of 1.5 ms, a repetition time of 5 s, and a proton
decoupling of 75 kHz. Solution NMR spectra were measured
on a Varian Inova 400 MHz NMR spectrometer at 400.0 MHz
(1H) and 100.580 MHz (13C). Energy dispersive X-ray analyses
were performed with an NCA X-Stream (Oxford Scientific)
system, coupled with a scanning electron microscope (SEM)
JEOL 6460LV. Each spectrum was acquired with a lifetime of
100 s (process time 5 s, spectrum range 0–20 keV, 2000
channels). All analyses were performed with an accelerating
voltage of 20 kV and 50–60 spot size. Elements were auto-
matically identified and quantified by the NCA system and
results were normalized. The system quantitative optimization
was realized with copper standard. The degrees of substitution
of polyligands were obtained from the C/N ratio obtained by
elemental analysis and correlated by the integration of the
resonances in the 1H NMR spectra. Metal coordination
degrees of substitution were calculated from Ru/O ratios from
EDS and correlated with 1H NMR spectroscopy. Enantiomeric
excesses were determined using a 30 m  0.25 mm b-DEX 110
column from Phenomenex using a gas chromatograph from
Agilent model 6850 with an Agilent mass detector model 5975B,
instrumentation control, data acquisitions and data processing
were done by Chemstation 1.5. The column temperature was
115 1C for 11 minutes and the carrier gas was helium. Retention
time and calibration for prochiral substrates and chiral products
were compared against standards from Aldrich.
21
32
58
22
23
22
9
62
0
24
25
7
30
—
20
26
27
26
55
—
—
Reactions were run in a 9 : 1 methanol to isopropanol ratio at 25 1C
under N2 for 24 hours with 120 equivalents of the substrate. The yields
and ees were determined by GC-MS on one run and calculated
assuming an equal response factor for all compounds. R and S product
identification is based on the phenylethanol results.
Dichloro(p-cymene)poly[b-(1-4)-2-deoxy-6-O-pivaloyl-D-
glucopyranose]Ru(II) 2–Ru
A yellow solution, containing 1 (0.07 g, 0.28 mmol of gluco-
pyranosyl units) in methanol (20 ml), was carefully added to a
solution containing Ru(p-cymene)Cl2 dimer (0.08 g, 0.14 mmol) in
methanol (15 ml). The resulting solution was stirred for 24 h under
nitrogen. The solution was ultrafiltered and washed with methanol
(300 ml). Methanol was removed and the solid dried under
vacuum. A pale orange solid film (2–Ru) in a yield of 74%
This report demonstrates that pivaloyl derivatized chitosan
2 can act as a support to ruthenium for the asymmetric
transfer hydrogenation of ketones using the intrinsic chirality
of a biopolymer as a chiral source. Although some drawbacks
need to be overcome, such as the degradation of the biopolymer
under basic conditions and the moderate enantiomeric excess, we
believe chitosan derivatives to be of interest in the development
of green technologies since it can serve as a soluble chiral support
for the synthesis of fine chemicals.
1
(0.108 g) was obtained. NMR H (CD3OD): d 5.7, 5.5, 5.4 (CH
p-cymene), 4.7–3.5 (pyranosyls), 2.8 (H2), 2.1 (CH3 para), 1.3 and
1.2 (CH3 isopropyl and pivaloyl) ppm. NMR 13C (CD3OD): d
178.4 (CQO ester), 100.8 (C1), 96.4 (CQC p-cymene), 79.0 and
78.3 (CH p-cymene), 77.0 (C4), 74.2 (C5), 71.0 (C3), 63 (C6), 56.3
and 55.0 (C2), 38.7 (C tert), 30.9 (CH iso), 22.2 and 21.0 (CH3 iso),
17.3 (CH3 para) ppm. EDS Ru/O ratio (mass/mass) calcd for
Experimental
Chitosan from Nordic shrimp (Pandalus borealis) shells with a
degree of deacetylation of 1.0 and a molecular mass of 567 kDa
C14.5H21.9NO5Ru0.35Cl0.7: 0.442, found: 0.422.
c
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Catalytic procedures
Y. Ben-David and D. Milstein, Angew. Chem., Int. Ed., 2011, 50,
2120–2124.
2–Ru (0.0010 g, 0.0018 mmol) was dissolved in methanol (0.3 ml)
and diluted with isopropanol (2.7 ml). The acetophenone
(0.1190 mmol) was then added and stirred for 5 minutes before
sodium isopropoxide (0.0074 g, 0.0900 mmol) was added. The
solution was immediately purged with nitrogen and kept under
an inert atmosphere and stirred. Aliquots (0.10 ml) were taken
with a syringe and diluted with isopropanol (0.9 ml). The top
layer was analyzed by GC-MS with an inlet and oven temperature
set at 115 1C. 1.0 ml samples were injected splitless onto the
column. Runs were conducted for 11 minutes. Retention times
are 6.5 min, 9.4 min and 9.9 min for acetophenone, R-2-phenyl-
ethanol, and S-2-phenylethanol, respectively.
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Acetophenone (0.0143 g, 0.120 mmol), R-2-phenylethanol
(0.0133 g, 0.108 mmol), and S-2-phenylethanol were each
dissolved in isopropanol (10.0 ml) as stock solutions. The
stock solutions were diluted 10, 100, 1000, and 10 000 times
and used as standards. A similar procedure was used for the
other ketones. High throughput procedures are detailed in the
ESI.w
We are grateful to NSERC (Canada), CFI (Canada),
FQRNT (Quebec), CCVC(Quebec), and CERPIC (Universite
´ ´ ´
Laval) for financial support. We would like to thank the CCRI
(University of Ottawa) for hosting FGF during the redaction
of the manuscript. MB would like to acknowledge NSERC
and FQRNT for scholarships.
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c
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New J. Chem., 2012, 36, 1548–1551 1551