Intramolecular acceleration of asymmetric epoxide ring-opening by dendritic polyglycerol salen-CrIII complexes

Article abstract of DOI:10.1002/ejoc.200900241

We present the synthesis of symmetrical (pyrrolidine-salen)Cr^III complexes immobilized on hyperbranched polyglycerol 1 through linkers of different lengths and their application in the asymmetric ring-opening of meso-epoxides. This reaction proceeded through a cooperative bimetallic mechanism and for the polymeric catalysts a positive dendritic effect with regard to the reaction rate was found. In addition, the introduction of long linkers (C6, Cl0, and C18) forced the favored head-to-tail orientation of two catalyst molecules and led to greater enantioselectivity with ee values of 48% (cyclohexene oxide) and 64 % (cyclopentene oxide) for the ring-opening of meso-epoxides with TMSN₃ catalyzed by hPG-C10CrCl (13). The soluble polyglycerol-supported catalyst was recovered five times by dialysis to afford similar activities and a 10% increase in the enantioselectivity.

Full text of DOI:10.1002/ejoc.200900241

FULL PAPER
DOI: 10.1002/ejoc.200900241
Intramolecular Acceleration of Asymmetric Epoxide Ring-Opening by
Dendritic Polyglycerol Salen–CrIII Complexes
Juliane Keilitz[a] and Rainer Haag*[a]
Dedicated to Professor Dr. Armin de Meijere on the occasion of his 70th birthday
Keywords: Supported catalysts / Ring opening / Dendrimers / Epoxides / Enantioselectivity / Chromium
We present the synthesis of symmetrical (pyrrolidine-salen)-
CrIII complexes immobilized on hyperbranched polyglycerol
1 through linkers of different lengths and their application in
the asymmetric ring-opening of meso-epoxides. This reaction
proceeded through a cooperative bimetallic mechanism and
greater enantioselectivity with ee values of 48% (cyclohex-
ene oxide) and 64% (cyclopentene oxide) for the ring-open-
ing of meso-epoxides with TMSN3 catalyzed by hPG-C10-
CrCl (13). The soluble polyglycerol-supported catalyst was
recovered five times by dialysis to afford similar activities
for the polymeric catalysts a positive dendritic effect with re- and a 10% increase in the enantioselectivity.
gard to the reaction rate was found. In addition, the introduc-
tion of long linkers (C6, C10, and C18) forced the favored
head-to-tail orientation of two catalyst molecules and led to
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
immobilize salen ligands and several attempts have been
made in this field.[1,20,21] In contrast to insoluble sup-
ports,[21] soluble ones are able to combine the best features
of heterogeneous supports (simplified separation from
small molecules and potential for recycling) with the advan-
tages of homogeneous synthesis (more normal reaction ki-
netics, higher reactivity and selectivity, lack of diffusion
phenomena, simple characterization) and allow the applica-
tion of continuous flow membrane techniques.[22]
Salen ligands have been immobilized on various soluble
polymeric supports, for example, non-crosslinked poly-
(styrene),[23,24] poly(norbornene),[7,25] and monomethylated
poly(ethylene glycol).[23] Dendritic structures are a special
kind of solid support. Their properties, compared with lin-
ear polymeric supports, such as good solubility, low vis-
cosity, and high density of the functional groups in their
periphery, make them very suitable as supports for cataly-
sis.[26] In particular, the high density of functional groups
on the surface can have a high impact on catalytic reactions,
for example, if they follow a cooperative bimetallic mecha-
nism,[27] which has been proven for the asymmetric ring-
opening (ARO) of epoxides with nucleophiles catalyzed by
chiral (salen)Cr complexes[10] and the hydrolytic kinetic res-
olution (HKR) of epoxides catalyzed by (salen)Co com-
plexes.[28]
Introduction
Enantioselective catalysis plays an important role in the
synthesis of chiral organic compounds in research, as well
as in the pharmaceutical and fine chemical industries. Met-
alated chiral salen ligands, for example, Jacobsen’s Mn cata-
lyst, are among the most successful asymmetric catalysts
today.[1,2] They were first introduced in the 1990s by Ja-
cobsen and Katsuki and their co-workers as highly enantio-
selective catalysts for the asymmetric epoxidation of un-
functionalized olefins.[3,4] Until today, their easy prepara-
tion and versatile catalytic performance, depending on the
nature of the chelated metal, made them “privileged” li-
gands.[5] Metalated salens have been prepared with a variety
of transition metals, including Mn, Cr, Co, V, Cu, Ti, Ru,
Pd, Au, Zn, and Al, and have been used for a multitude of
asymmetric organic transformations, for example, the epox-
idation of olefins,[4,6,7] the ring-opening of epoxides,[8–11] hy-
drolytic kinetic resolution of epoxides,[12–15] conjugate ad-
dition reactions to α,β-unsaturated imides,[16] (hetero)-
Diels–Alder reactions,[17–19] and many others.[1]
Owing to the cost of the catalysts, which usually exceeds
the value of the products, and the challenge to simplify
product purification from metal residues, it is desirable to
[a] Institute of Chemistry and Biochemistry, Freie Universität
Berlin,
The two reactions follow the same mechanism, with two
different catalytic moieties activating the epoxide and nu-
cleophile simultaneously.[10] Because of this mechanism, a
close proximity of the (salen)metal complexes, which can be
achieved by a covalent connection of two salen units or by
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-838-53357
E-mail: haag@chemie.fu-berlin.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900241.
3272
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Intramolecular Acceleration of Asymmetric Epoxide Ring-Opening
attachment of catalyst molecules to a dendritic support,
should lead to a rate enhancement of these reactions (Fig-
ure 1). This has already been shown for the ARO of epox-
ides with dimers of (salen)Cr complexes[8] as well as for the
HKR of epoxides with oligomeric[14] or macrocyclic (salen)-
Co complexes[13] or (salen)Co complexes immobilized on
PAMAM[28] or gold nanoparticles.[15] If dendritic structures
are involved, this effect on the catalytic reaction is called a
positive dendritic effect.
Figure 2. Part of the structure of hyperbranched polyglycerol (1,
hPG).
has been used before in our group,[19] but because the salen
ligand builds up on the support this approach suffers from
ill-defined catalyst species on the polymer, because full con-
version of all functional groups on the polymer cannot be
guaranteed. Owing to the labile nature of the imine bond,
synthesis of the unsymmetrical salen ligand leads to mix-
tures of symmetrical and unsymmetrical ligands and low
yields are obtained.
The symmetrical approach utilizes the symmetrical pyr-
rolidine-salen ligand 2, which is easily synthesized starting
from (R,R)-(+)-tartaric acid[8,33] and can be coupled to 1
through the N atom in the backbone of the ligand.
For the synthesis of immobilized pyrrolidine-salen deriv-
atives, 1 with Mn = 6000 gmol–1 was used and either acti-
vated with phenyl chloroformate to form the mixed carbon-
ate (30% functionalization) or the OH groups of 1 were
transformed into amines (hPG-amine, 55% functionaliza-
tion).[29]
Figure 1. Representation of the simultaneous activation of epoxide
and nucleophile by a) monomeric (intermolecular) and b) dendritic
systems[28] (intramolecular).
Because perfect dendrimers are expensive and very te-
dious to synthesize, we recently developed the hyper-
branched polyglycerol 1 (hPG; Figure 2) as a soluble den-
dritic support for organic synthesis[29,30] and catalysis.[19,31]
This polyether polyol can be synthesized on a kilogram-
scale by ring-opening polymerization of glycidol[32] and
contains linear monohydroxy and terminal dihydroxy func-
tional groups, which can be easily converted by standard
synthetic methods. Its versatile properties, such as high-
loading capacity (13.5 mmolg–1), good solubility in a wide
range of solvents (depending on the functional groups in
the periphery), chemical stability, and noncoordinating
properties, make it a promising support for reagents and
catalysts, especially metal complexes.
Herein we present the synthesis of hPG-supported com-
plexes of salen analogues with a pyrrolidine backbone, their
application to the ARO of meso-epoxides with trimethylsilyl
azide (TMSN3), and their recycling by membrane filtration.
Pyrrolidine-salen (2) can be coupled directly to hPG-
phenyl carbonate (Scheme 1) and chromium was inserted as
described before.[19] Purification by preparative gel permea-
tion chromatography (GPC) and full characterization by 1H
and 13C NMR and IR spectroscopy was performed on the
hPG-C1-pyrrolidine-salen ligand 3. For the final metal
complex 4 only IR spectroscopy and ICP-MS (inductively
Results and Discussion
There are two possible approaches to the covalent immo- coupled plasma mass spectrometry) were used for charac-
bilization of salen ligands on hPG (1); the symmetrical and terization because, due to the paramagnetic nature of chro-
the unsymmetrical method. The unsymmetrical approach mium, NMR methods cannot be applied.
Scheme 1. Synthesis of hPG-C1-CrCl (4).
Eur. J. Org. Chem. 2009, 3272–3278
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J. Keilitz, R. Haag
FULL PAPER
To construct a comparable monomeric catalyst we de- 9 h. The reaction time for Jacobsen’s catalyst of 24 h lies
cided to synthesize the Boc-protected (pyrrolidine-salen)- between the two (pyrrolidine-salen)Cr catalysts. This be-
chromium complex 5 because the protecting group mimics comes even clearer when the rate plots (Figure 4) are taken
the linker used to attach pyrrolidine-salen 2 to hPG 1. The into consideration. The highest rate constant is obtained for
monomeric catalyst 5 (Figure 3) was synthesized from the the polymer-supported ligand 4 (Table 1, Entry 1), and is
known Boc-protected pyrrolidine-salen[34] by chromium in- one order of magnitude higher than that of Boc(pyrrolid-
sertion.[19]
ine-salen)CrCl (5) (Entry 2) and approximately three times
higher than that of Jacobsen’s CrCl complex (Entry 3).
Table 1. Results for the ARO of cyclohexene oxide with TMSN3
with catalysts 4–6.[a]
Catalyst (R,R)-configuration Rate constant [s–1][b] Time [h][c]
8.772ϫ10–5
6.664ϫ10–6
2.995ϫ10–5
8.6
54.9
23.6
Figure 3. Structures of the monomeric Boc(pyrrolidine-salen)CrCl
5 and Jacobsen’s catalyst 6.
1
2
3
hPG-C1-CrCl (4)
Boc(pyrr.-salen)CrCl (5)
Jacobsen’s catalyst (6)
The catalyst hPG-C1-CrCl (4), its monomeric counter-
part 5, and the commercially available Jacobsen’s chromium
catalyst (6, see Figure 3) were used in the ARO of cyclohex-
ene oxide with TMSN3 (method A; reaction conditions as
in ref.[9]). First we wanted to prove that immobilization of
salen analogues on a dendritic support leads to a significant
rate enhancement for this reaction in comparison with the
monomeric catalysts. This positive dendritic effect can be
clearly observed from the conversion vs. time plots shown
in Figure 4.
[a] Reaction conditions: method A, 2 mol-% of chromium catalyst.
[b] Rate constants calculated from the slope of the rate plots in
Figure 4 (b). [c] Time extrapolated from the last measuring point
before 100% conversion.
Because it is known that the active species is not the chlo-
ride but the azide complex 7[9,10] (Figure 5), we developed
a new method (method B) in which the azide complex is
formed in situ before addition of the substrate to avoid an
initial activation time.
Figure 5. Catalytically active species of (salen) analogues in the
ARO of meso-epoxides.
For this purpose the “precatalyst” 4 was stirred with
TMSN3 for 16 h for the counterion exchange to occur. In
the ARO of cyclohexene oxide this resulted in an additional
rate enhancement for all three catalysts and under the same
conditions the reaction catalyzed by 4 was finished after 6 h
[rate constants, 4: 1.875ϫ10–4 s–1, 5: 3.931ϫ10–5 s–1, and
6: 7.992ϫ10–5 s–1].
Concerning the enantioselectivities, it is quite clear that
the hPG-supported catalyst 4 performs much worse than
the monomeric catalysts 5 and 6 (Table 2, Entries 1–3). By
method A, at a catalyst loading of 2 mol-%, the two mono-
mers 5 and 6 catalyze the ARO of cyclohexene oxide with
similar ee values of around 65%, whereas 4 achieves an ee
of only 12%. Lowering the catalyst loading to 0.5 mol-%
results in an increase of ee to 21% (Entry 3) for the reaction
Figure 4. Conversion vs. time (a) and rate plots (b) for the ARO of
cyclohexene oxide with TMSN3 with hPG-C1-CrCl (4) (᭿), Boc-
(pyrrolidine-salen)CrCl (5) (᭡), and Jacobsen’s catalyst (6) (᭹)
(method A; for catalyst 5 the next measuring point was 120 h with
100% conversion).
Whereas the Boc(pyrrolidine-salen)CrCl complex needs catalyzed by 4. The ee values obtained with Boc(pyrrolid-
approximately 55 h to reach full conversion, the reaction ine-salen)CrCl remain more or less the same (Entries 4–6),
with hPG-supported analogue 4 was completed after only but for Jacobsen’s catalyst 6 they drop dramatically to 30%
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Intramolecular Acceleration of Asymmetric Epoxide Ring-Opening
for a catalyst loading of 0.5 mol-% (Entry 9). Application
of method B results in slightly higher enantioselectivities
of around 70% for 5 (Table 2, Entries 4–6), whereas with
Jacobsen’s catalyst ee values of 41–51% were obtained (En-
tries 7–9). In contrast, the ee values achieved with the sup-
ported catalyst 4 are at all catalyst loadings around 30%
higher than with method A (Entries 1–3) with a 28% ee for
a loading of 0.5 mol-% (Entry 3). It has already been re-
ported by Jacobsen and co-workers[35] that the azide com-
plex in some cases catalyzes with higher enantioselectivity,
but the increase they observed was not as high as the rise
we observed.
Figure 6. Azide complex of hPG-C1-CrCl (4) and the expected
head-to-head orientation of the catalytic units during the coopera-
tive catalysis.
Table 2. Enantioselectivities for the ARO of cyclohexene oxide with
TMSN3; comparison of methods A and B for different catalyst
loadings.
C18) were mono-activated with phenyl chloroformate and
coupled to the secondary amine of the pyrrolidine-salen li-
gand 2. Subsequently, activation of the second hydroxy
group of the linker was achieved with phenyl chloroformate
and the resulting modified pyrrolidine-salen ligands 10a–
c were coupled to hPG-amine (Scheme 2) and purified by
preparative GPC.
Catalyst
R,R configuration
Loading
[mol-%] Method A Method B
ee [%][a]
1
2
3
4
5
6
7
8
9
hPG-C1-CrCl (4)
2
1
12
16
21
18
22
28
70
72
73
51
44
41
hPG-C1-CrCl (4)
hPG-C1-CrCl (4)
0.5
2
1
Boc(pyrr.-salen)CrCl (5)
Boc(pyrr.-salen)CrCl (5)
Boc(pyrr.-salen)CrCl (5)
Jacobsen’s catalyst (6)
Jacobsen’s catalyst (6)
Jacobsen’s catalyst (6)
68
67
0.5
2
1
74
65
All nonpolymeric compounds were fully characterized by
1H and 13C NMR spectroscopy, ESI-MS, elemental analy-
sis, and IR spectroscopy. The hPG-supported ligands were
64
0.5
30[b]
1
characterized by H and 13C NMR, and IR spectroscopy.
[a] Determined by chiral GC. The S,S enantiomer is in excess. [b]
A second experiment gave 27% ee.
After chromium insertion the metal complexes 12–14 were
characterized by IR spectroscopy and ICP-MS (see
Scheme 2).
The enantioselectivities obtained with the hPG-sup-
When catalysts 12–14 were applied to the ARO of cyclo-
ported system 4 are still very low and can be explained by hexene oxide with TMSN3 the rate enhancement of the
a “negative dendritic effect”, which results from the orienta- polymeric systems was retained and it was observed that the
tion of the immobilized catalytic units with respect to one introduction of linkers of different lengths leads to higher
another. It has been reported in the literature that there are enantioselectivities (Table 3).
two possible orientations of the catalyst molecules, one is
The best catalyst is hPG-C10-CrCl (13) with the linker
the so-called “head-to-head” arrangement and the second derived from 1,10-decanediol. At a catalyst loading of
the “head-to-tail” orientation in which one catalyst unit is 1 mol-% it achieved the highest ee of 48% (Table 3, En-
turned around by 180°.[8] Through the construction of salen try 3). This was also supported by the results of the ARO
dimers, it was shown that the head-to-tail arrangement is of cyclopentene oxide with TMSN3 (Table 4). With the ex-
necessary to achieve high enantioselectivities, whereas the ception of hPG-C1-CrCl (7), all polymeric catalysts pro-
head-to-head arrangement led to an ee of only 8%.[8]
duced higher enantioselectivities, but it is known from the
For hPG-C1-CrCl (4) we expect a head-to-head arrange- literature that epoxides fused to five-membered rings afford
ment because the linker is very short and the hyper- higher enantioselectivities than their six-membered ring an-
branched polymer can be assumed to have a globular struc- alogues.[9] In Table 4 (Entry 3) it can be seen that 13 again
ture. Therefore most of the interactions that take place on presents the best performance, affording an ee of 64%.
the polymer surface should match the head-to-head ar- From these results we can conclude that C10 is the correct
rangement, as indicated in Figure 6.
length for the expected back-folding (Figure 7).
To achieve higher enantioselectivities we decided to in-
To prove the recyclability, 4 was reused in five consecu-
troduce linkers of different lengths between the pyrrolidine- tive cycles and the product was separated from the poly-
salen ligand 3 and the polymeric support. With a long meric catalyst 4 successfully by dialysis. For the last two
enough linker we hoped to enable back-folding of the cata- cycles the conversion slightly decreased to 97%, which indi-
lytic unit, which should lead to the favored head-to-tail ori- cates that the catalyst is slowly losing activity, but at the
entation and therefore to higher enantioselectivities. For same time the enantioselectivity increased from 20 (Table 5,
this purpose α,ω-diols of different lengths (C6, C10, and 1st run) to 30% (5th run). The chemical yields after work-
Eur. J. Org. Chem. 2009, 3272–3278
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3275

J. Keilitz, R. Haag
FULL PAPER
Scheme 2. Synthesis of hPG-supported pyrrolidine-salen ligands 11a–c and their corresponding chromium complexes 12, 13, and 14.
Table 3. Results of the ARO of cyclohexene oxide with TMSN3.[a]
Catalyst
R,R configuration
ee [%][b]
2 mol-% 1 mol-% 0.5 mol-%
1
2
3
4
5
6
hPG-C1-CrCl (4)
18
31
39
35
70
51
22
36
48
43
72
44
28
36
44
44
73
41
hPG-C6-CrCl (12)
hPG-C10-CrCl (13)
hPG-C18-CrCl (14)
Boc(pyrr.-salen)CrCl (5)
Jacobsen’s catalyst (6)
[a] Performed by method B. [b] Determined at three levels of cata-
lyst loading by chiral GC. The S,S enantiomer is in excess.
Figure 7. Possible back-folding mechanism for the favored head-
to-tail orientation with a C10 linker.
Table 4. Results of the ARO of cyclopentene oxide with TMSN3.[a]
Table 5. Recycling of hPG-C1-CrCl (4) in the ARO of cyclohexene
oxide with TMSN3.[a]
1st run
2nd run 3rd run 4th run 5th run
Conversion [%][b]
ee [%][c]
Ͼ99
20
97
Ͼ99
27
95
Ͼ99
22
89
99
28
77
3.8
97
30
75
2.4
Catalyst R,R configuration
ee [%][b]
Yield [%][d]
Metal leaching [ppm][e]
8.4
7.6
3.9
1
2
3
4
5
6
hPG-C1-CrCl (4)
16
47
64
56
81
85
hPG-C6-CrCl (12)
hPG-C10-CrCl (13)
hPG-C18-CrCl (14)
Boc(pyrr.-salen)CrCl (5)
Jacobsen’s catalyst (6)
[a] 1 mol-% catalyst; 1st run method B, 2nd–5th run method A. [b]
Determined by GC. The S,S enantiomer is in excess. [c] Deter-
mined by chiral GC. [d] After column chromatography. [e] Deter-
mined by ICP-MS.
[a] Performed by method B with a catalyst loading of 1 mol-%. [b]
Determined by chiral GC. The S,S enantiomer is in excess.
Conclusions
We have shown that dendritic polymers are suitable for
the immobilization of catalysts that interact by a coopera-
up decrease after the 3rd run, which indicates that separa- tive bimetallic mechanism. The close proximity of pyrroli-
tion by dialysis is becoming less effective. Here the applica- dine-salen 2 at the periphery of a hyperbranched polygly-
tion of continuously operating systems can improve the per- cerol was used to force the cooperative catalysis in the
formance of the process and has promise because of the low asymmetric ring-opening of meso-epoxides with TMSN3,
metal leaching of the catalyst into the product.
which led to an increase in the rate constant by one order
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Intramolecular Acceleration of Asymmetric Epoxide Ring-Opening
3.23 mmol) and hPG-phenyl carbonate[29] (2.79 mmolg–1 carbon-
ate groups, 1.16 g, 3.23 mmol, 1.0 equiv.) were heated at reflux in
dry pyridine (10 mL) for 2 d. The solvent was removed in vacuo
and the crude product was purified by preparative GPC to yield
921 mg (46%) of a glassy orange foam.
of magnitude compared with the monomeric analogue 5.
By introducing different length linkers (C6, C10, and C18)
between hPG and the (pyrrolidine-salen)CrCl complex we
improved the enantioselectivity by a factor of two, with a
maximum for the catalyst with the C10 linker. This was
ascribed to a partial back-folding of the catalytic units,
which leads to the favored head-to-tail orientation and
therefore to higher ee values of up to 48% for cyclohexene
oxide and 64% for cyclopentene oxide by catalysis with
hPG-C10-CrCl. Recycling of the catalyst was successfully
achieved five times by dialysis with very low metal leaching
of the catalyst into the product, revealing a slight loss of
activity, and an increase in the ee by 10% from the 1st to
the 5th run. Investigations into the application of the poly-
meric catalyst in a continuously operating membrane reac-
tor are in progress.
Supporting Information (see also the footnote on the first page of
this article): Complete experimental details and characterization
data for compounds 3–5 and 8–14.
Acknowledgments
We thank Dipl.-Ing. Winfried Münch for HPLC separations and
Dipl.-Ing. Thomas Wons for ICP-MS measurements.
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General Procedure (GP) A. Mono-Activation of α,ω-Diol with
Phenyl Chloroformate: α,ω-Diol (1.0 equiv.) and TEA (5.0 equiv.)
were dissolved in THF (p.a.). Phenyl chloroformate (1.0 equiv.) in
THF was added dropwise over 30 min and the mixture was stirred
for 18 h. The precipitated TEA·HCl salt was removed by filtration,
the solvent was removed under vacuum, and the residue was puri-
fied by column chromatography.
General Procedure B. Coupling of ω-Hydroxyalkyl Phenyl Carbon-
ate to Pyrrolidine-Salen 3: This reaction was performed under dry
conditions. Pyrrolidine-salen ligand
2 (1.0 equiv.) and ω-hy-
droxyalkyl phenyl carbonate 8a–c (2.0 equiv.) were dissolved in dry
pyridine and the mixture was heated at reflux for 17–21 h (conver-
sion was monitored by TLC). The solvent was removed in vacuo
and the crude product was purified by HPLC. When only a small
excess of the ω-hydroxyalkyl phenyl carbonate was used, the prod-
uct could be purified by column chromatography.
General Procedure C. Activation of ω-Hydroxyalkyl-1-(pyrrolidine-
salen): This reaction was performed under dry conditions. ω-Hy-
droxyalkyl-1-(pyrrolidine-salen) 9a–c and TEA (5.0 equiv.) were
dissolved in dry THF and phenyl chloroformate (2.0 equiv.) was
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for 18 h, the solvent was removed in vacuo, and the crude product
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Published Online: May 13, 2009
3278
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Eur. J. Org. Chem. 2009, 3272–3278