Glycosylation initiated cationic ring-opening polymerization of tetrahydrofuran to prepare neo-glycopolymers

Article abstract of DOI:10.1039/c0cc00566e

An unprecedented and highly efficient glycosylation initiated cationic ring-opening polymerization (CROP) of tetrahydrofuran is disclosed employing glycosyl ortho-hexynylbenzoates as donors and gold(i) as a catalyst, that provides an easy access to novel glycopolymers which could self-assemble into nanostructures.

Full text of DOI:10.1039/c0cc00566e

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www.rsc.org/chemcomm | ChemComm
Glycosylation initiated cationic ring-opening polymerization
of tetrahydrofuran to prepare neo-glycopolymersw
Yao Li and Biao Yu*
Received 24th March 2010, Accepted 8th July 2010
DOI: 10.1039/c0cc00566e
An unprecedented and highly efficient glycosylation initiated
cationic ring-opening polymerization (CROP) of tetrahydrofuran
is disclosed employing glycosyl ortho-hexynylbenzoates as donors
and gold(I) as a catalyst, that provides an easy access to novel
glycopolymers which could self-assemble into nanostructures.
minimized.7a Occasionally, when we mixed 3,4,6-tri-O-acetyl-
2-azido-2-deoxy-D-glucopyranosyl ortho-hexynylbenzoate (1a)
with PPh3AuOTf (0.3 equiv.) in deuterated tetrahydrofuran
(THF-d8) at room temperature (rt) with stirring (in the absence
of an acceptor), we found surprisingly that the clear solution
turned quickly into a turbid and viscous one which gelled heavily
1
after standing overnight. H NMR measurement of the gel-like
Complex carbohydrates are major organic components which
in association with proteins and lipids constitute structural
matrices and scaffolds critical for life processes. Especially, the
extruding epitopes of carbohydrates play important roles in
various recognition processes such as fertilization, development,
immune responses, infection, and metastasis.1 However,
efficacious chemical methods to understand and manipulate
the carbohydrates still lag far behind those available for the
other two fundamental biopolymers, i.e., nucleic acids and
peptides.2 Highly simplified synthetic glycopolymers, which
could assemble into a variety of nanostructures, have thus
been explored in attempting to extrapolate certain functions of
the native carbohydrates to materials applicable in the field of
biomedicine, such as in drug delivery, tissue engineering,
biosensors, and separation technology.3,4 Glycopolymers
bearing carbohydrates as pendant moieties have been
prepared via polymerization of carbohydrate-containing
monomers or post-modification of reactive precursor polymers
using those well-established reactions.4 More difficult to
synthesize are the carbohydrate-headed polymers; besides
post-modification of a polymer bearing a functional group at
termini,5 living radical polymerization with a carbohydrate-
derived initiator has mainly been exploited,6 in that either a
difficult-to-complete polymer reaction or an instable initiator
is involved. Herein, an innovative method for the convenient
preparation of glycopolymers with a carbohydrate glycosidically
linked at the termini of polytetrahydrofuran is reported.
We recently developed an efficient glycosylation protocol
with glycosyl ortho-alkynylbenzoates (1, Fig. 1) as donors and
a gold(I) complex as catalyst, in that the activation mechanism
is unprecedented for the generation of the glycosyl
oxocarbeniums A, which then react with nucleophilic acceptors
to provide the desired glycosides.7 A prominent feature of
this new reaction is the reluctance of the promoter (e.g.,
PPh3AuNTf2 or PPh3AuOTf in catalytic amounts) and the
leaving entity (i.e., the isocoumarin B) to interfere with the
cationic glycosylation processes, thus side reactions are
solid (dissolved in CDCl3) showed the clear conversion of 1a into
a pair of the glycosides (a:b = 1 : 1) and isocoumarin B.
Workup of the reaction (by dissolving in CH2Cl2, washing with
H2O, and removal of the solvent under high vacuum) led to a
white plastic solid, which was characterized to be a glycosyl
polytetrahydrofuran (G-PTHF, 2a).8
The above results were unexpected but could be rationalized
easily. Cationic ring-opening polymerization (CROP) of THF
has been well practised since the 1930s;9 a plethora of cationic
species such as oxonium ions, carbenium ions, strong protic
acids, and Lewis acids could initiate the reaction.10 On the
other hand, glycosylation reaction involving glycosyl
oxocarbeniums is at times performed in THF. However, the
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China.
E-mail: byu@mail.sioc.ac.cn; Fax: (0086)-21-64166128
w Electronic
Experimental details, characterization data, and NMR spectra. See
DOI: 10.1039/c0cc00566e
Fig. 1 Glycosylation initiated cationic ring-opening polymerization
(CROP) of THF with glycosyl ortho-hexynylbenzoates as donors and
gold(I) as a catalyst.
supplementary
information
(ESI)
available:
c
6060 Chem. Commun., 2010, 46, 6060–6062
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glycosyl oxocarbenium initiated polymerization of THF has
never been recorded. Understandably, even in the absence of
an acceptor (for instance, during the pre-activation procedure)11
or in the presence of a very poorly nucleophilic acceptor,
promoters (mostly being used in over stoichiometric amounts)
or the leaving entities in the conventional glycosylation
systems could sequester or destroy quickly the transient
oxocarbenium species. In fact, the only relevant example was
reported by Gervay-Hague and coworkers, in that glycosyl
iodides reacted with THF to afford the corresponding
4-iodo-butyl glycosides,12 where the leaving iodide Iꢀ prevented
the polymerization.
Fig. 2 The number-average molecular weight (Mn), the molecular
weight distribution (Mw/Mn) of the resulting G-PTHF as a function of
time in the CROP of THF initiated by 1a–1e, respectively.
carbohydrate derivatives and were shelf-stable.8 Under the
above-mentioned conditions ([1] = 0.01 mol Lꢀ1 in THF,
0.5 equiv. PPh3AuNTf2, rt, quenched with H2O), the growing
Mn of the resulting G-PTHF and the corresponding MWD
(Mw/Mn) as a function of time are depicted in Fig. 2. All these
glycosyl donors could initiate the polymerization of THF
efficiently, with the ‘super-arming’13 2-O-benzoyl-3,4,6-tri-O-
benzyl-D-glucopyranosyl ortho-hexynylbenzoate 1c being the
most active initiator. The CROP was fast at the beginning
(o15 min) and was then affected by the increasing viscosity of
the reaction mixture; end-biking might take place. In fact, the
present initiation system is even more efficacious than most of
those previously reported, where the Mn of the resulting
PTHF are mostly below 2 ꢁ 104.10 The functional groups,
including the acetyl (Ac), benzoyl (Bz), benzyl (Bn), phthaloyl
(Phth), and azide group, and the glycosidic linkages as well,
were intact in the polymerization reaction.z
We then examined in detail this glycosylation initiated
polymerization of THF with perbenzoyl glucopyranosyl
ortho-hexynylbenzoate 1b as the donor, which would lead to
the b-anomeric linkage exclusively due to the neighboring
group participation in the glycosylation initiation, and the
stable and commercially available PPh3AuNTf2 as a catalyst
(Table 1).7a The initiation was fast and highly efficient; at
3 min, the starting 1b (0.01 mol Lꢀ1 in THF) was almost
completely incorporated into the growing G-PTHF as
1
evidenced by H NMR analysis of the reaction mixture. The
conversion of THF into G-PTHF increased gradually, from
2.1% (wt%) at 3 min up to 19% at 2 d, when the reaction
mixture turned highly viscous and the stirring could not
continue. The molecular weight of the resulting G-PTHF
increased from Mn = 8968 at 3 min to 73 820 at 2 d. The
molecular weight distribution (MWD) was narrow at the
beginning (Mw/Mn = 1.15 at 3 min) but broadened gradually
(up to 1.65 at 65 min), in accordance with the increasing
viscosity of the reaction mixture. When the starting
concentration of 1b was increased to 0.04 mol Lꢀ1, 60%
conversion of THF could be reached (entry 9); while at
[1b] = 0.005 mol Lꢀ1, the final conversion was 8% (entry 8).
As control experiments, the gold catalyst or the glycosyl
ortho-hexynylbenzoate 1b alone could not initiate the
polymerization of THF.
The G-PTHFs, after removal of the protecting groups on
the sugar moiety, are amphiphilic, thus could self-assemble
into nanostructures in solutions.3,5d,6c,d Thus, trisaccharide-
PTHF 2e (Mn = 1.9 ꢁ104, Mw/Mn = 1.24) was subjected to
removal of the acetyl groups on the carbohydrate moiety
(NaOMe, MeOH, rt) to provide the trisaccharide-PTHF 3
quantitatively. Nano-sized spherical particles were assembled
upon evaporation of a THF–MeOH solution of the trisaccharide-
PTHF 3 (M = 0.1 mg mLꢀ1) on a silicon plate, as observed by
atomic force microscopy (AFM) (Fig. 3). G-PTHF 3,
although its hydrophilic trisaccharide moiety constitutes
only B3% of the molecular weight, could disperse into water
to form a stable colloidal solution (as evidenced by the
observation of the Tyndall effect) via charging of a THF
solution of 3 (0.1 mg mLꢀ1, 0.2 mL) into water (5 mL)
followed by evaporation of the THF. Formation of spherical
particles was also observed on a silicon surface under AFM.
However, the detailed structure and potential applications of
these nano-assemblies await further studies.
A brief investigation of the scope of this polymerization was
then performed using a panel of glycosyl ortho-hexynylbenzoates
as donors, including monosaccharides 1a/1c, disaccharide 1d,
and trisaccharide 1e. These glycosyl ortho-hexynylbenzoates
were easily prepared from the corresponding 1-OH
Table 1 Glycosylation initiated CROP of THF with 2,3,4,6-tetra-O-
benzoyl-D-glucopyranosyl ortho-hexynylbenzoate (1b) as the donora
d
d
Entry
[1b]b
Time
Conv.c
Mn
Mw
Mw/Mn
1
2
3
4
5
6
7
8
9
0.01
3 min
9 min
17 min
28 min
65 min
120 min
2 d
2.1%
4.6%
7.1%
8.3%
9.1%
10.6%
19.0%
8%
8968
10 354
21 622
33 354
42 297
48 365
49 670
100 625
82 580
59 630
1.15
1.23
1.33
1.50
1.65
1.58
1.36
1.63
1.82
In conclusion, an efficient glycosylation initiated CROP of
THF has been disclosed using the easily accessible and shelf-
stable glycosyl ortho-hexynylbenzoates as donors and gold(I)
as catalyst. Novel G-PTHFs with carbohydrate residues
glycosidically linked at one end could be easily prepared.
End-capping with various nucleophiles would be able to
generate G-PTHFs bearing an additional functional group
at the other end;10b,d multi-armed G-PTHFs could also thus be
prepared with multi-valent nucleophiles.10e In addition, the
present glycosylation initiated CROP of THF could be
followed by co-polymerization with other monomers, such
as glycidol,10f to prepare glycopolymers with a variety of
17 561
25 181
28 179
29 295
31 346
73 820
50 586
32 727
0.005
0.04
2 d
2 d
60%
a
In the presence of PPh3AuNTf2 (0.5 equiv.) at rt and quenched with
b
cold water. The starting concentration of donor 1b in THF
(mol Lꢀ1). The conversion of THF into G-PTHF (wt%). Determined
by gel permeation chromatography (GPC) based on polystyrene
standards.
c
d
c
This journal is The Royal Society of Chemistry 2010
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Fig. 3 AFM image of the trisaccharide-PTHF 3, casting from
THF–MeOH (v : v = 1 : 1) (M = 0.1 mg mLꢀ1) on a silicon surface.
backbones. Synthesis of those novel glycopolymers and
studies on their nanostructures and functions have emerged
as interesting future projects.
We are grateful for financial support from the National
Natural Science Foundation of China (20932009 and
20621062) and the E-Institutes of Shanghai Municipal
Education Commission (E09013).
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Notes and references
8 See Supporting Information for details.
z General procedure for the glycosylation initiated CROP of THF.
Under an argon atmosphere, to a stirring solution of 3,4,6-tri-O-
acetyl-2-azido-2-deoxy-D-glucopyranosyl ortho-hexynylbenzoate 1a
(206 mg, 0.4 mmol) in dry THF (35 mL) at room temperature was
added a THF solution of PPh3AuNTf2 (0.2 mmol, 5 mL). After
different reaction times, the mixture was poured into ice cold water.
The resulting G-PTHF 2a was precipitated, which was then taken
from the solution and dried under vacuum. For small scale analysis, a
sample was taken from the reaction mixture via syringe and charged
into cold water. The resulting aqueous solution was concentrated to
give a residue, which was then purified by silica gel column chromato-
graphy (petroleum ether/EtOAc 3 : 1 to CH2Cl2–MeOH 25 : 1) to
provide the G-PTHF 2a. The G-PTHF could also be purified by gel
column Sephadex LH-20 (CH2Cl2–MeOH 1 : 1) or precipitation from
N,N-dimethylformamide.
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c
6062 Chem. Commun., 2010, 46, 6060–6062
This journal is The Royal Society of Chemistry 2010