6060 Chem. Commun., 2010, 46, 6060–6062 This journal is c The Royal Society of Chemistry 2010

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.

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

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

after standing overnight. 1H NMR measurement of the gel-like

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

Fig. 1 Glycosylation initiated cationic ring-opening polymerization

(CROP) of THF with glycosyl ortho-hexynylbenzoates as donors and

gold(I) as a catalyst.

State Key Laboratory of Bioorganic and Natural Products Chemistry,Shanghai Institute of Organic Chemistry, Chinese Academy ofSciences, 354 Fenglin Road, Shanghai 200032, China.E-mail: byu@mail.sioc.ac.cn; Fax: (0086)-21-64166128w Electronic supplementary information (ESI) available:Experimental details, characterization data, and NMR spectra. SeeDOI: 10.1039/c0cc00566e

COMMUNICATION www.rsc.org/chemcomm | ChemComm

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This journal is c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 6060–6062 6061

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 I� prevented

the polymerization.

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 L�1 in THF) was almost

completely incorporated into the growing G-PTHF as

evidenced by 1H 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 L�1, 60%

conversion of THF could be reached (entry 9); while at

[1b] = 0.005 mol L�1, 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.

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

carbohydrate derivatives and were shelf-stable.8 Under the

above-mentioned conditions ([1] = 0.01 mol L�1 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.zThe 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 mL�1) 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 mL�1, 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.

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

Table 1 Glycosylation initiated CROP of THF with 2,3,4,6-tetra-O-benzoyl-D-glucopyranosyl ortho-hexynylbenzoate (1b) as the donora

Entry [1b]b Time Conv.c Mnd Mw

d Mw/Mn

1 0.01 3 min 2.1% 8968 10 354 1.152 9 min 4.6% 17 561 21 622 1.233 17 min 7.1% 25 181 33 354 1.334 28 min 8.3% 28 179 42 297 1.505 65 min 9.1% 29 295 48 365 1.656 120 min 10.6% 31 346 49 670 1.587 2 d 19.0% 73 820 100 625 1.368 0.005 2 d 8% 50586 82 580 1.639 0.04 2 d 60% 32727 59 630 1.82

a In the presence of PPh3AuNTf2 (0.5 equiv.) at rt and quenched with

cold water. b The starting concentration of donor 1b in THF

(mol L�1). c The conversion of THF into G-PTHF (wt%). d Determined

by gel permeation chromatography (GPC) based on polystyrene

standards.

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.

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6062 Chem. Commun., 2010, 46, 6060–6062 This journal is c The Royal Society of Chemistry 2010

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).

Notes and references

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 wasadded a THF solution of PPh3AuNTf2 (0.2 mmol, 5 mL). Afterdifferent reaction times, the mixture was poured into ice cold water.The resulting G-PTHF 2a was precipitated, which was then takenfrom the solution and dried under vacuum. For small scale analysis, asample was taken from the reaction mixture via syringe and chargedinto cold water. The resulting aqueous solution was concentrated togive a residue, which was then purified by silica gel column chromato-graphy (petroleum ether/EtOAc 3 : 1 to CH2Cl2–MeOH 25 : 1) toprovide the G-PTHF 2a. The G-PTHF could also be purified by gelcolumn Sephadex LH-20 (CH2Cl2–MeOH 1 : 1) or precipitation fromN,N-dimethylformamide.

1 Essentials of Glycobiology, ed. A. Varki, R. D. Cummings,J. D. Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hartand M. E. Etzler, Spring Harbor Laboratory Press, N.Y., 2nd edn,2009.

2 (a) P. H. Seeberger, Nat. Chem. Biol., 2009, 5, 368; (b) T. J. Boltje,T. Buskas and G.-J. Boons, Nat. Chem., 2009, 1, 611.

3 S. F. M. van Dongen, H.-P. M. de Hoog, R. J. R. W. Peters,M. Nallani, R. J. M. Nolte and J. C. M. van Hest, Chem. Rev.,2009, 109, 6212.

4 For selected reviews on glycopolymer synthesis, see: (a) M. Okada,Prog. Polym. Sci., 2001, 26, 67; (b) V. Ladmiral, E. Melia andD. M. Haddleton, Eur. Polym. J., 2004, 40, 431; (c) A. J. Varma,J. F. Kennedy and P. Galgali, Carbohydr. Polym., 2004, 56, 429;(d) S. G. Spain, M. I. Gibson and N. R. Cameron, J. Polym. Sci.,Part A: Polym. Chem., 2007, 45, 2059.

5 For selected examples, see: (a) K. Loos and A. H. E. Muller,Biomacromolecules, 2002, 3, 368; (b) W. T. E. Bosker, K. Agoston,M. A. C. Stuart, W. Norde, J. W. Timmermans and T. M. Slaghek,Macromolecules, 2003, 36, 1982; (c) J. Rieger, F. Stoffelbach,D. Cui, A. Imberty, E. Lameignere, J.-L. Putaux, R. Jerome,C. Jerome and R. Auzely-Velty, Biomacromolecules, 2007, 8,2717; (d) C. Schatz, S. Louguet, J.-F. Le Meins andS. Lecommandoux, Angew. Chem., Int. Ed., 2009, 48, 2572.

6 For selected examples, see: (a) K. Yasugi, T. Nakamura,Y. Nagasaki, M. Kato and K. Kataoka, Macromolecules, 1999,32, 8024; (b) D. M. Haddleton and K. Ohno, Biomacromolecules,2000, 1, 152; (c) M. J. Joralemon, K. S. Murthy, E. E. Remsen,M. L. Becker and K. L. Wooley, Biomacromolecules, 2004, 5, 903;(d) C. Houga, J.-F. Le Meins, B. Redouane, D. Taton andY. Gnanou, Chem. Commun., 2007, 3063.

7 (a) Y. Li, X. Yang, Y. Liu, C. Zhu, Y. Yang and B. Yu,Chem.–Eur. J., 2010, 16, 1871; (b) Y. Li, Y. Yang and B. Yu,Tetrahedron Lett., 2008, 49, 3604.

8 See Supporting Information for details.9 (a) H. Meerwein, G. Hinz, P. Hoffman, E. Kroning and E. Pfeil,J. Prakt. Chem., 1937, 147, 257; (b) H. Meerwein, D. Delfs andH. Morschel, Angew. Chem., 1960, 72, 927.

10 For selected examples, see: (a) B. J. McCarthy and T. E.Hogen-Esch, Macromolecules, 1996, 29, 3035; (b) E. Yoshida andA. Sugita, Macromolecules, 1996, 29, 6422; (c) M. F. Dubreuil,N. G. Farcy and E. J. Goethals, Macromol. Rapid Commun., 1999,20, 383; (d) H. Oike, Y. Yoshioka, S. Kobayashi, M. Nakashima,Y. Tezuka and E. J. Goethals, Macromol. Rapid Commun., 2000,21, 1185; (e) L. M. van Renterghem, E. J. Goethals and F. E. duPrez, Macromolecules, 2006, 39, 528; (f) S. Theiler, T. Hovetborn,H. Keul and M. Moller, Macromol. Chem. Phys., 2009, 210, 614.

11 For examples, see: (a) D. Crich and S. Sun, J. Am. Chem. Soc.,1997, 119, 11217; (b) S. Yamago, T. Yamada, T. Maruyama andJ.-I. Yoshida, Angew. Chem., Int. Ed., 2004, 43, 2145;(c) X. Huang, L. Huang, H. Wang and X.-S. Ye, Angew. Chem.,Int. Ed., 2004, 43, 5221.

12 D. R. Dabideen and J. Gervay-Hague, Org. Lett., 2004, 6, 973.13 L. K. Mydock and A. V. Demchenko, Org. Lett., 2008, 10, 2103.

Fig. 3 AFM image of the trisaccharide-PTHF 3, casting from

THF–MeOH (v : v = 1 : 1) (M = 0.1 mg mL�1) on a silicon surface.

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