Poly(vinyl alcohol)-graft-poly(ethylene glycol) resins and their use in solid-phase synthesis and supported TEMPO catalysis

Article abstract of DOI:10.1039/b700215g

New poly(vinyl alcohol)-graft-poly(ethylene glycol) (PVA-g-PEG) resins with various PEG chain lengths, which have high loadings and good swelling both in water and organic solvents, have been prepared via an anionic polymerization of ethylene oxide onto PVA beads and applied in solid-phase synthesis, supported TEMPO catalysis and in HR-MAS ¹H NMR spectral analysis. The Royal Society of Chemistry.

Full text of DOI:10.1039/b700215g

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Poly(vinyl alcohol)-graft-poly(ethylene glycol) resins and their use in
solid-phase synthesis and supported TEMPO catalysis{
Juntao Luo, Christophe Pardin, William D. Lubell* and X. X. Zhu*
Received (in Cambridge, UK) 8th January 2007, Accepted 6th February 2007
First published as an Advance Article on the web 28th February 2007
DOI: 10.1039/b700215g
2
1
New poly(vinyl alcohol)-graft-poly(ethylene glycol) (PVA-
g-PEG) resins with various PEG chain lengths, which have
high loadings and good swelling both in water and organic
solvents, have been prepared via an anionic polymerization of
ethylene oxide onto PVA beads and applied in solid-phase
loading (15–17 mmol g ) and good swelling in water and
19–21
N,N-dimethylformamide (DMF).
By grafting short PEG
chains onto the PVA core, novel amphiphilic supports possessing
chemically stable C–C and C–O–C bonds, high loading and
optimal swelling properties in a variety of solvents have now been
synthesized and employed in solid-phase synthesis and solid
supported catalysis in aqueous and organic solvents.
1
synthesis, supported TEMPO catalysis and in HR-MAS H
NMR spectral analysis.
Crosslinked PVA beads that exhibited good mechanical stability
were prepared by employing dimethyl sulfoxide (DMSO) as a co-
solvent for solvating the more hydrophobic epichlorohydrin
As new strategies in combinatorial chemistry and solid supported
1–4
chemistry emerge,
new solid supports are required having
effective loading of functional groups and good swelling in a
5
variety of solvents (including aqueous solutions). Crosslinked
crosslinker and the alkalized aqueous solution of linear PVA in
19–22
a modification of our previously published procedure.
Anionic
6
polystyrene-divinylbenzene (PS-DVB) matrices have been the
polymerization of ethylene oxide was used to graft PEG onto PVA
resin in a controlled fashion to provide PVA-PEG resins 2
possessing various chain lengths (Scheme 1). Naphthalene
potassium was used as base for deprotonating the OH groups
on the PVA beads to generate alkoxide anions which initiate the
ring opening polymerization of ethylene oxide on the resins.
Spherical and free-flowing PVA-PEG resins were observed by
optical microscopy with sizes of 30–100 mm in diameter and PVA-
PEG beads have a smooth surface as observed under scanning
electron microscopy (Fig. 1). The PVA resins can be made with
proven paradigm in solid-phase chemistry to produce peptides and
small molecules. The hydrophobic PS backbone has, however,
poor compatibility with aqueous and polar solvents and is
generally unsuitable for on-bead magic angle spinning (MAS)
7
NMR analysis. Poly(ethylene glycol) (PEG) has been used to
improve swelling and overcome the shortcomings of the PS-DVB
resins for use in water and polar solvents, with the development of
11–14
and PEG cross-linked resins.
8–10
PEG-grafted PS-DVB resins
The rigidity and hydrophobicity of the PS-DVB core necessitated
grafting long PEG chains (.3 kDa) to optimize hydrophilicity
20
different porosity by adjusting the degree of crosslinking. The
2
1
with the inherent drawback of lowered loading (0.2–0.5 mmol g ).
size of the PVA-PEG beads resembled that of the PVA beads
selected for the anionic polymerization. The mechanical properties
21
Contemporary PEG crosslinked resins also have normally low
21 15
loading (0.2–0.4 mmol g
)
and may possess sensitive benzyl
of the PVA resins have been studied previously. The PVA-PEG
ether and amide bonds that restrict certain chemistry. As an
alternative to PEG, polyglycerol was grafted onto PS resin to
resins were mechanically stable in the swollen state, and very
resistant to shaking and mechanical stirring. The new resins were
unaffected by treatments with 6 M HCl and with 6 M NaOH,
showing good chemical stability. The hydroxyl group loadings
21
increase loading (up to 4.3 mmol g ) and improve swelling in
21 16
water (up to 2.6 mL g ). However, a relatively low grafting
yield and the presence of both primary and secondary alcohols
that may exhibit different reactivities are drawbacks to this
19–22
21
were titrated with Ac O
2
to be 6.2, 3.4 and 2.0 mmol g for
the PVA-PEG resins with 5, 12 and 20 PEG units, respectively, in
reasonable agreement with theoretical loadings calculated from
21
17–19
strategy. High-loading resins are effective scavengers
and offer
promise for a variety of chemistry. High loading on a PS-derived
resin with high swelling in a wide range of media has yet to be
achieved, because of the restrictions of the hydrophobic PS-DVB
core.
mass gain (6.7, 3.6 and 2.1 mmol g , respectively). PEG-grafted
PVA resin 2 displayed increased swelling in less polar solvents
relative to PVA resin 1, and uniformly higher swelling in a variety
In a new approach for making resins with high loading and
good swelling in a variety of solvents, we have grafted PEG
chains onto a crosslinked poly(vinyl alcohol) (PVA) core. The
hydrophilic PVA resins are mechanically-stable and possess high
D e´ partement de Chimie, Universit e´ de Montr e´ al, C.P. 6128, Succ.
Centre-ville, Montr e´ al, QC, H3C 3J7, Canada.
E-mail: julian.zhu@umontreal.ca; Fax: (01-514)340-5290;
Tel: (01-514)340-5172
{
Electronic supplementary information (ESI) available: Experimental
details for the characterization of the resins, the solid-phase reactions and
TEMPO oxidation. See DOI: 10.1039/b700215g
Scheme 1 Preparation of PVA-PEG resin 2 and peptide synthesis.
This journal is ß The Royal Society of Chemistry 2007
2
136 | Chem. Commun., 2007, 2136–2138

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Fig. 1 Optical (left, in water) and scanning electron micrographs (right,
dry) of PVA-PEG resin 2 with five PEG units.
of solvents in comparison with TentaGel, Merrifield and Wang
resins (Fig. 2).
The utility of the PVA-PEG resin was demonstrated first by the
2
3
synthesis of the transglutaminase substrate dipeptide 4 (Z-Gln-
Gly-NH ) on PVA-PEG_5 resin in 98% isolated yield and 92%
purity as ascertained by LC-MS analysis (Scheme 1).
Scheme 2 Preparation of PVA-PEG-supported TEMPO catalyst 9 for
alcohol oxidations and of Wang linker resin 10.
2
24
Considering the advantages of high loading for solid supported
catalysis in aqueous and organic media, the catalyst 2,2,6,6-
Table 1 Bleach/DCM alcohol oxidation with TEMPO resin 9
25
tetramethylpiperidinyloxy (TEMPO) radical was next attached
c
Conv. (%) Yield (%)
Alcohol 11
Product 12 Time
onto PVA-PEG_5 resin 2 using the Cu(I)-catalyzed [2 + 3] dipolar
26,27
cycloaddition reaction
(Scheme 2) between a polymer-
a
5
min 100
98
supported azide 6 and an alkyne-derivatized TEMPO species 7.
TEMPO resin 9 catalyzed efficiently alcohol oxidations to
aldehydes and ketones in a biphasic bleach/dichloromethane
a
3
3
0 min 100
87
90
21
(DCM) media likely due to its high loading (1.8 mmol g by
nitrogen elemental analysis) and effective swelling in both DCM
and water. TEMPO resin 9 floated at the interface between DCM
and water. Such physical properties are considered to enhance
catalytic activity by facilitating the transfer of the reaction
intermediates between the two phases. A series of primary and
secondary alcohols were subjected to the PVA-PEG-TEMPO/
bleach/DCM oxidation (Table 1) for 5 to 240 min and the
corresponding carbonyl compounds were isolated by simple
filtration and phase separation in 80–98% yields. The recycling
property of TEMPO resin 9 was examined with benzyl alcohol and
monitored by thin layer chromatography (TLC). After twelve
cycles of repeated catalysis, the time for complete oxidation of
benzyl alcohol to benzaldehyde increased from 5 to 18 min,
indicating relatively stable catalytic performance.
a
0 min 100
a
b
3
0 min 100
86
80
4
4
h
h
96
b
99
87
a
b
Monitored by TLC. Determined by H NMR. Isolated yields.
1
c
A PVA-PEG Wang linker resin 10 was similarly made by
dipolar cycloaddition using p-propargyloxy benzyl alcohol 8 and
2
4
azide resin 6 with PEG chains of 20 units (Scheme 2). The MAS
1
H NMR spectrum of PVA-PEG Wang resin 10 in DMF-d
Fig. 3) exhibited relatively high resolution of the proton signals of
7
(
the resin matrix and linker. The splittings of the aromatic proton
doublets were observed to be 6.5 Hz at 7.50 and 7.22 ppm.
Furthermore, the PVA-PEG matrix exhibited a main signal
around 3.6 ppm and three weak signals between 1.0 and 2.0 ppm,
which may avoid overlaps with signals from supported structures
Fig. 2 Swelling of PVA, PVA-PEG and commercial resins as ascertained
by weighing beads saturated with absorbed solvent. Merrifield (2% DVB
2
1
crosslinking, 100–200 mesh, 2.0 mmol g loading) and Wang resins (1%
2
1
DVB crosslinking, 100–200 mesh, 1.0 mmol g loading) were purchased
2
1
from Fluka, and Tenta Gel S OH resin (90 mm, 0.2–0.3 mmol g loading)
1
from Rapp Polymere GmbH.
during on-bead HR-MAS H NMR analysis.
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Chem. Commun., 2007, 2136–2138 | 2137

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1
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Fig. 3 HR-MAS H NMR (600 MHz, nanoprobe spin rate: 6 kHz,
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In summary, a novel effective approach for producing high-
loading resins with high uniform swelling in aqueous and organic
solvents has been developed by grafting PEG chains onto
hydrophilic PVA core. The new resins were suitable for on-bead
MAS NMR analysis and possessed attributes for solid-phase
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21
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Qu e´ bec (VRQ) and the Canada Research Chair program is
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{
Preparation of PVA-PEG resin 2: All glassware and needles were flame-
dried under vacuum and purged three times with nitrogen. PVA beads 1
0.4 g) were placed into a 100 mL flask, equipped with a Dean–Stark trap,
4
1
(
1
containing 20 mL of dry benzene and heated under reflux overnight to
remove the water–benzene azeotrope. Benzene was distilled off under
vacuum and 25 mL of dry DMSO was charged into the flask to swell the
PVA resin. A calibrated amount of potassium naphthalene in THF
2
21 M. A. Gauthier, J. T. Luo, D. Calvet, C. Ni, X. X. Zhu, M. Garon and
M. D. Buschmann, Polymer, 2004, 45, 8201.
(0.45 M, 6 mL, 0.45 eq.) was introduced dropwise into the flask using a
2
2 X. X. Zhu, J. T. Luo, W. D. Lubell and C. Pardin, US Pat., US60/
04664, 2006.
3 S. M. F. G. Gillet, R. A. Chica, J. W. Keillor and J. N. Pelletier, Protein
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double-tip needle and argon pressure. The mixture was stirred for 2 h to
allow the green color from the naphthalene potassium to completely
disappear. Ethylene oxide of a known volume was passed through a
calcium hydride drying-column and condensed into a dry flask containing
8
2
2
4 Longer peptides have been synthesized on PVA-PEG resin 2 and Wang
linker resin 10, and will be described in a full account of this research.
25 For TEMPO catalyst, see a recent review: P. L. Bragd, H. van Bekkum
and A. C. Besemer, Top. Catal., 2004, 27, 49.
2
mL of n-butyllithium (1.6 M) solution in hexane at 278 uC. The dry ice/
acetone bath was removed and, as the flask warmed, ethylene oxide was
distilled into the resin suspension which was cooled to 278 uC. Once the
transfer of ethylene oxide was completed, the polymerization mixture was
heated and magnetically stirred at 40 uC for 48 h. The resin was filtered off
and rinsed with water and THF and subsequently extracted successively
with THF and water using a Soxhlet extractor for 24 h per solvent. The
beads were finally freeze-dried for 48 h to give copolymer resin 2 and stored
below 5 uC under nitrogen.
I
26 For Cu -catalyzed alkyne-azide click cycloadditions, see a recent review:
V. D. Bock, H. Hiemstra and J. H. van Maarseveen, Eur. J. Org. Chem.,
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27 S. Lober, P. Rodriguez-Loaiza and P. Gmeiner, Org. Lett., 2003, 5,
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2
138 | Chem. Commun., 2007, 2136–2138
This journal is ß The Royal Society of Chemistry 2007