Aqueous asymmetric cyclopropanation reactions in polymersome membranes

Article abstract of DOI:10.1039/c3cc48865a

Copper-bis(oxazoline) complexes have been immobilised in the hydrophobic domain of a polymersome membrane to perform asymmetric cyclopropanation reactions in aqueous media with enhanced conversions and enantioselectivities. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc48865a

Volume 50 Number 31 21 April 2014 Pages 4013–4136
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Floris P. J. T. Rutjes, Jan C. M. van Hest et al.
Aqueous asymmetric cyclopropanation reactions in polymersome
membranes

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Aqueous asymmetric cyclopropanation reactions
in polymersome membranes†
Cite this: Chem. Commun., 2014,
50, 4040
Matthijs C. M. van Oers, Loai K. E. A. Abdelmohsen, Floris P. J. T. Rutjes* and
Jan C. M. van Hest*
Received 20th November 2013,
Accepted 13th January 2014
DOI: 10.1039/c3cc48865a
www.rsc.org/chemcomm
Copper-bis(oxazoline) complexes have been immobilised in the hydro-
Inspired by these results, we developed a strategy for the
phobic domain of a polymersome membrane to perform asymmetric immobilisation of a copper-bis(oxazoline) catalyst inside a
cyclopropanation reactions in aqueous media with enhanced con- polymersome membrane. Polymersomes, artificial vesicles con-
versions and enantioselectivities.
sisting of amphiphilic block copolymers, have emerged as
powerful nanoreactors in the last few years.9 A recent publication
Chiral bis(oxazoline)-metal complexes have been used extensively by our group shows the ability of polymersomes to form Pickering
in the past decades in asymmetric cyclopropanation reactions.1 emulsions, in which a biphasic biocatalytic reaction could be
This popularity can be attributed to their excellent activities and realised.10 We also reported a one-pot cascade reaction which was
selectivities for a broad range of substrates.2 However, application achieved by selective compartmentalization of three different
of these catalysts in aqueous systems is rather troublesome.3 enzymes in a polymeric vesicle.11 Extension of this methodology
Unstable transition states, undesired side-reactions and low solu- to transition-metal catalysts would increase the versatility of these
bilities for both substrates and catalysts make water an unfavour- vesicles and pave the way for future metal- and biocatalysed
able solvent, despite its many apparent advantages. In the past few cascade reactions. Furthermore, we reasoned that affixation of
years progress has been made in overcoming incompatibility issues the catalyst inside the hydrophobic domain of the bilayer would
between homogeneous transition-metal catalysts and water. yield a protective environment in which the catalyst and the
Research groups have designed nanoreactors consisting of homo- substrates are shielded from external influences. Herein we report
geneous metal catalysts immobilised on polymeric supports that the synthesis of cross-linked polymeric vesicles functionalised with
could perform various catalytic reactions in aqueous systems, chiral bis(oxazoline)-copper catalysts. We show that these catalytic
i.e. cross-coupling reactions,4 hydrolytic kinetic resolutions5 and polymersomes have a positive effect on the rate and enantioselectivity
asymmetric allylic substitutions.6 Regardless of the great merit of of asymmetric cyclopropanation reactions in water. Moreover, we
their work, alternative synthetic pathways in water already exist for prove that the polymeric nanoreactors exhibit substrate selectivity
most of these reactions. Asymmetric cyclopropanation reactions, based on the hydrophobicity of the starting alkene.
on the other hand, often require a metal–carbene complex, which
In order to provide an anchor for chiral bis(oxazoline)-
poses a great challenge on the design of the catalyst in water. copper catalysts inside the hydrophobic bilayer, we designed
Recently, Carreira and coworkers7 developed a hydrophobic a poly(ethylene glycol)-b-poly-(styrene-co-4-vinylbenzyl azide)
iron(III)–porphyrin complex capable of performing cyclopropanation (PEG-b-P(S-co-4-VBA)) polymer. Since azide moieties are not stable
reactions between olefins and in situ generated diazomethane in at elevated temperatures during polymerization, we started off
6 M KOH. Arnold and coworkers8 further exploited the catalytic with the synthesis of a poly(ethylene glycol)-b-poly-(styrene-co-4-
nature of iron porphyrins and engineered a cytochrome P450 vinylbenzyl chloride) (PEG-b-P(S-co-4-VBC)) polymer. A PEG44
enzyme that could catalyse the reaction between styrene and chain transfer agent was prepared which was used to polymerise
ethyl diazoacetate in water with high enantiomeric selectivity.
styrene and 4-vinylbenzyl chloride (4-VBC) via reversible addition–
fragmentation chain-transfer polymerization (RAFT).12 We chose
a 90 : 10 ratio between styrene and 4-VBC as the initial monomer
composition to offer sufficient handles for catalyst loading and
at the same time ensure the integrity of the polymeric bilayer.
Subsequent post-modification of the polymer with NaN3
provided (PEG-b-P(S-co-4-VBA)) polymer P1 with a number-
average molecular weight (Mn) of 19.5 kDa and a PDI of 1.31
Institute for Molecules and Materials, Radboud University Nijmegen,
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
E-mail: j.vanhest@science.ru.nl, f.rutjes@science.ru.nl
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc48865a
4040 | Chem. Commun., 2014, 50, 4040--4043
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To confirm the integrity of the polymersomes after function-
alisation they were analysed by Transmission Electron Microscopy
(TEM, Fig. S10a, ESI†) and Cryogenic Scanning Electron Micro-
scopy (Cryo-SEM, Fig. S10b, ESI†). Fig. S10a (ESI†) shows the
spherical morphology of the polymeric vesicles, while the cross
section shown in Fig. S10b (ESI†) reveals their empty inner cavity.
The thickness of the membrane was estimated to be 25–35 nm.
Dynamic light scattering (DLS, Fig. S9, ESI†) studies proved that the
diameter of the vesicles did not change after functionalisation, with
an average diameter of 450–500 nm. The distribution of copper in
the polymersomes was characterised by Energy-Dispersive X-ray
(EDX) Spectroscopy. The overlap between the copper signal in
the X-ray map (Fig. S10c, ESI†) and the contours of the vesicles
in the Scanning Transmission Electron Microscopy (STEM)
image (Fig. S10d, ESI†) demonstrate the highly localised
concentration of copper in the polymersome bilayer. The copper
loading of the functionalised polymersomes was 93% (determined
by Inductively Coupled Plasma Mass Spectrometry (ICP-MS)).
With these functionalised polymersomes in hand we continued
with an assessment of the catalytic activity. The polymersomes were
employed in a test reaction between styrene and ethyl diazoacetate
at a copper concentration of 10 mol%. Reaction times were
limited to 10 minutes, which was sufficient to reach a maximum
conversion, while polymersome precipitation occurring after
prolonged reaction times was prevented. After extraction with
CH2Cl2 the cyclopropane products could be recovered in a yield
of 54% (Table 1, entry 2). This result could not be obtained with
Fig. 1 Chemical structures of azide-functionalised block copolymers and
modified Cu-bis(oxazoline) catalysts (top) and a schematic representation
of a Cu-bis(oxazoline) loaded polymersome (bottom).
(determined by Multiangle Laser Light Scattering (MALLS) and non-functionalised polymersomes, indicating that the observed
1H-NMR, see Fig. S1 and S4, ESI†).
activity is due to the presence of the copper-bis(oxazoline)
Next we investigated the introduction of a Cu(II)-bis(4- catalyst (entry 4). To optimise the catalytic performance of the
phenyl-2-oxazoline) catalyst, which has proven to give high yields polymersomes, two different catalysts C2 and C3 were synthe-
and enantioselectivities in asymmetric cyclopropanation reactions. sised. Despite the slightly lower yield of polymersomes loaded
To prepare the catalyst for immobilisation via a Copper(I)-catalysed with catalyst C2, the enantioselectivity significantly improved,
Azide–Alkyne Cycloaddition (CuAAC) reaction,13 2,20-methylene- making this catalyst superior to catalysts C1 and C3 (entries 5 and 6).
bis[(4S)-4-phenyl-2-oxazoline] had to be modified with an alkyne These results are in correspondence with previous studies, in
functionality. This was achieved by deprotonation of the methylene which the activity of the different catalysts in organic solvents
bridge with BuLi, followed by alkylation with propargyl bromide. was investigated.1b To evaluate the effect of the catalyst loading
We envisioned that double alkylation at this position would not in the polymersomes, we prepared block copolymers P2 and P3
only preserve the C2-symmetry of the catalyst, but would also in which 5% and 20%, respectively, of the styrene monomers
result in a fully cross-linked system, which would increase were functionalised with an azide handle. Applying both polymers
the stability of the polymersomes during extraction. After in a catalytic assay between styrene and ethyl diazoacetate did not
coordination with Cu(OTf)2, catalyst C1 was obtained in an lead to an increase in conversion nor in enantioselectivity (entries 7
overall yield of 66% (Fig. 1).
and 8). This made us decide to continue further experiments with
The polymeric vesicles were prepared by the cosolvent method.14 catalyst C2 and polymer P1.
Ultrapure water was slowly added to a solution of block copolymer
To put these results into perspective we performed a study in
P1 in THF until a H2O : THF ratio of 50% was reached. During the which the catalytic activity of our catalytic polymersomes was
addition the solution changed from colourless to turbid, indicating compared with the activity of catalyst C2 in Milli-Q and CH2Cl2.
the presence of polymersomes. Next, a solution of catalyst C1 in THF Much to our satisfaction, the conversion we obtained for the
was added, together with CuSO4ꢀ5H2O, bathophenanthroline catalytic polymersomes was comparable with the conversion of
sulfonated sodium salt and ascorbic acid. The CuAAC reaction the parent catalyst in CH2Cl2 (entry 9), even when this last
was monitored by Fourier Transform Infrared (FTIR) spectro- reaction was allowed to stir for two hours. However, employing
scopy. After stirring for 3 days at room temperature, the azide catalyst C2 in Milli-Q provided cyclopropane product 1 in a
peak at 2095 cmꢁ1 completely disappeared (Fig. S8, ESI†). The much lower yield (entry 10). Furthermore, under these reaction
polymersomes were subsequently transferred to a dialysis conditions the enantioselectivity decreased significantly to 35%
membrane and dialysed against ultrapure water for 72 hours while this was not the case for our catalytic polymersomes. A similar
to remove THF and the CuAAC catalyst.
study with catalyst C1 yielded comparable results (entries 11 and 12).
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Table 1 Asymmetric cyclopropanation reaction of styrene derivatives and ethyl diazoacetatea
Entry
R
Solvent
Rxn time (min)
Loadb (mol%)
Catalyst
Polymer
Conv.c,d (%)
trans/cisd
ee transe (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
OMe
Cl
tBu
COOH
NH2
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CH2Cl2
H2O
CH2Cl2
H2O
H2O
H2O
H2O
H2O
H2O
120
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
2
C1
C1
C1
—
P1
P1
P1
P1
P1
P1
P2
P3
—
—
—
—
P1
P1
P1
P1
P1
50 f
54
12
0
39
43
31
29
40
9
53
12
93i
32i
67i
3
73/27
74/26
72/28
—
60
60
60
—
0
10
10
10
10
10
10
10
10
10
10
10
10
10
C2
C3
C2
C2
C2
C2
C1
C1
C2
C2
C2
C2
C2
68/32
59/41
70/30
71/29
70/30
67/33
72/28
72/28
68/32
75/25
67/33
nd
84
34g
85
87
86
35
64
26
59h
53h
71
nd
nd
9
10
11
12
13
14
15
16 j
17
0
nd
a
Reactions were carried out in Milli-Q or CH2Cl2 (3.0 mL) at room temperature using styrene (0.46 mmol, 5.0 equiv.) and ethyl diazoacetate
(0.092 mmol, 1.0 equiv.). Catalyst loading in mol%. Conversion of ethyl diazoacetate into a cyclopropane product. Determined by 1H-NMR
spectroscopy of crude product, using triethylene glycol dimethyl ether as an internal standard. Determined by chiral GC. Polymersomes started
to precipitate after 15 min. Configuration of the product was (1S,2S). Determined by chiral HPLC. Isolated yields. Substrate was solubilised
b
c
d
e
f
g
h
i
j
by addition of Et3N (0.46 mmol, 5.0 equiv.).
These observations indicate that the catalyst inside the polymer- Immobilisation of a Cu-bis(oxazoline) catalyst inside the poly-
somes is surrounded by a hydrophobic environment from which mersome membrane via a CuAAC reaction allowed for stability
water is excluded, since water is affecting both the conversion and and a good control over the catalyst loading. Furthermore, the
the enantioselectivity of the asymmetric cyclopropanation reaction. hydrophobic environment around the catalyst was demonstrated by
In order to investigate the scope of our catalytic polymersomes substrate selectivity. Hydrophobic substrates were readily converted
we screened a series of alkenes for the asymmetric cyclopropanation into the corresponding cyclopropane products, while hydrophilic
reaction (Table 1, entries 13–17). According to our expectations the substrates did not undergo any reaction. This makes these catalytic
yield increased when a more activated alkene was used (entry 13), polymersomes a promising alternative for the asymmetric
while it dropped when a more electron-deficient alkene was applied cyclopropanation reaction of hydrophobic alkenes in organic
(entry 14). The presence of a bulky substituent did not hamper the solvents. We envision that encapsulating enzymes inside the
reaction, but led to a higher yield instead (entry 15). A remarkable lumen of these polymeric vesicles will extend this methodology
effect was observed when we changed the hydrophilicity of the and produce multifunctional nanoreactors, capable of perform-
alkene. 4-Vinylbenzoic acid virtually did not produce any cyclo- ing cascade reactions in a tandem manner.
propane product, even when it was solubilised with triethyl-
This work was financially supported by the Netherlands
amine (entry 16). To prove that the low yield could not be ascribed Research School Combination Catalysis (NRSCC). We thank
to the electron-poor nature of the alkenes, we performed an asym- Geert-Jan Janssen for his assistance with cryo-SEM and EDX.
metric cyclopropanation reaction with 4-aminostyrene. The intrinsic
Notes and references
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concentrator effect.5,15 The hydrophobicity of styrene (log P = 3.05)
leads to an increased local concentration around the catalyst and
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In conclusion, we have developed a polymersome nanoreactor
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