Regioselective and quantitative modification of cellulose to access cellulose-based advanced materials: Cellulose-based glyeoclusters

Article abstract of DOI:10.1246/cl.2009.122

Regioselective and quantitative introduction of multiple β-lactoside modules onto the 6C-position of cellulose was achieved through regioselective bromination/azidation of cellulose and the following Cu⁺-catalyzed chemoselective coupling with a

Full text of DOI:10.1246/cl.2009.122

122
Chemistry Letters Vol.38, No.2 (2009)
Regioselective and Quantitative Modification of Cellulose to Access Cellulose-based
Advanced Materials: Cellulose-based Glycoclusters
Erika Yamashita,1 Kiyomi Okubo,1 Kaori Negishi,1 and Teruaki Hasegawaꢀ1;2
1Department of Life Sciences, Faculty of Life Sciences, Toyo University,
1-1-1 Izumino, Itakura-machi, Ora-gun, Gunma 374-0193
2Bio-Nano Electronics Research Centre, Toyo University, 2100 Kujirai, Kawagoe 350-8585
(Received November 12, 2008; CL-081069; E-mail: t-hasegawa@toyonet.toyo.ac.jp)
Regioselective and quantitative introduction of multiple
ꢀ-lactoside modules onto the 6C-position of cellulose was
achieved through regioselective bromination/azidation of cellu-
lose and the following Cuþ-catalyzed chemoselective coupling
with alkyne-functionalized ꢀ-lactoside. The resultant cellulose-
based glycocluster has good water solubility and selective lectin
affinity.
Cellulose (ꢀ-1,4-glucan) is one of the most promising can-
didates of ecomaterials, since it is abundant in nature and bio-
degradable. It should be also noted that the cellulose is also ad-
vantageous as a substrate for chiral materials and, for example,
silica gels coated with cellulose derivatives are now widely used
as stationary phase for chiral separation.1 In spite of these great
possibilities, chemical modification of cellulose, that is, the very
first step to access cellulose-based fine materials, still contains
tedious obstacles. Cellulose consists of many hydroxy function-
alities having similar reactivity towards electrophiles; therefore,
regioselective reaction is rarely accomplished. To the best of our
knowledge, no regioselective/quantitative approach to access
functionalized celluloses has been reported so far.2
Recently, a general synthetic approach toward functional-
ized curdlan (ꢀ-1,3-glucan) based on a two-step strategy was es-
tablished: that is, (1) 6C-selective and quantitative bromination/
azidation of curdlan to afford 6-azido-6-deoxycurdlan (CUR–
N3) and (2) the subsequent click chemistry-based functionaliza-
tion of CUR–N3 using alkyne-terminated functional modules.3
This methodology is quite useful to develop curdlan-based
cell-specific DNAs/RNAs carriers and unique carbon nanotubes
solubilizers.4 In this manuscript, we report the application of this
synthetic methodology to cellulose chemistry to develop cellu-
lose-based fine materials.
Cellulose (DPn 280) was dissolved into N,N-dimethyl-
acetoamide (DMA) containing LiCl by stirring at 80 ꢁC for
24 h and then converted into 6-bromo-6-deoxycellulose (Cel–
Br) through 6C-selective bromination using triphenylphosphine
and carbon tetrabromide (Scheme 1). 13C NMR spectrum of
Cel–Br was too noisy to be assigned because of low solubility
in DMSO-d6. We, therefore, carried out the next reaction with-
out detailed characterization of Cel–Br. The subsequent azida-
tion was attained by treating Cel–Br with NaN3 in a mixed
DMA/DMSO solvent system at 85 ꢁC for 40 h to afford 6-
azide-6-deoxycellulose (Cel–N3). It should be noted that solubil-
ity of these cellulose derivatives drastically changes, that is, Cel–
Br is soluble in DMA but hardly soluble in DMSO and Cel–N3 is
less soluble in DMA but well-soluble in DMSO. When we car-
ried out this azidation in DMA solution throughout the reaction,
Scheme 1. 6C-Selective bromination/azidation of cellulose to
affords Cel–N3 and the subsequence introduction of ꢀ-lacto-
side-modules onto cellulose scaffold through click chemistry.
partially azidated cellulose was precipitated, and perfect conver-
sion from Cel–Br to Cel–N3 was never achieved. We therefore
started the azidation in DMA solution and then suitably added
DMSO to the reaction mixture to keep the mixture homogene-
ous. Quantitative and regioselective azidation was confirmed
by 13C NMR spectrum, in which the peaks assignable to 6C–Br
(44.43 ppm) entirely disappear and that of 6C–N3 (50.66 ppm)
newly appears. Furthermore, no unassignable peak arising from
random modification was observed, strongly indicating homoge-
neous chemical structure along the cellulose main chain. We
would like to emphasize that this is the first example of regiose-
lectively/quantitatively modified cellulose derivatives.
Although Cel–N3 with homogeneous repeating units was
obtained as mentioned above, the azide functionality has no
practical (protein recognition, light harvesting, etc.) function,
and, therefore, Cel–N3 itself can find little practical application.
On the contrary, Cel–N3 can give full scope to its ability when it
is used as a template for further modification toward functional
cellulose-based materials. To establish easy and general method-
ology for the further modification, click chemistry, that is, Cuþ-
catalyzed cycloaddition of alkyne-terminated functional mod-
ules onto Cel–N3 was applied.5 Since this reaction is exclusively
chemoselective, tolerant for various coexisting functionalities,
and applicable to various solvent systems, various cellulose-
based advanced materials having desired functions can be devel-
oped from Cel–N3.
The introduction of functional modules onto Cel–N3 to
develop advanced cellulose-based materials is exemplified by
using an oligosaccharide as a functional module. Since the
oligosaccharides are specific ligands for various carbohydrate-
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.2 (2009)
123
binding proteins, various synthetic polymers having multiple
copies of carbohydrate appendages (glycoclusters) developed
so far show strong and specific affinity for these proteins. The
cellulose derivatives having multiple copies of oligosaccharides
appendages should find, therefore, potential applications in ther-
apeutic purposes. In this work, we introduced ꢀ-lactoside, or a
specific ligand for asiallo-glycoprotein receptor (AGPR), onto
the cellulose scaffold to afford cellulose-based glycoclusters.
In a small vial, Cel–N3 was dissolved into DMSO and al-
kyne-terminated ꢀ-lactoside (ꢀLac–yn), CuBr2, ascorbic acid,
and n-propylamine were added. After being kept at room tem-
perature overnight, the resultant reaction mixture was dialyzed
(water, MWCO8000) and lyophilized to afford a cellulose deriv-
ative having ꢀ-lactoside-appendages at all 6C position along the
cellulose main chain (Cel–ꢀLac). It should be emphasized that
this coupling procedure is quite easy and that no rigorous condi-
tion (inert atmosphere and/or anhydrous condition, etc.) are re-
quired. This advantage should remove a barrier for nonspecial-
ists of organic synthesis and accelerate participation in develop-
ment of cellulose-based functional materials. Furthermore, it is
also of great advantage that this coupling reaction can be carried
out in DMSO that is an excellent solvent for various polar and
nonpolar substrates. This fact ensures the wide application of
our synthetic procedure to various polar/nonpolar, organic/
inorganic functional modules. The 13C NMR spectrum of Cel–
ꢀLac shows peaks assignable to cellulose main chain, ꢀ-lacto-
side appendages, and linker moieties including a 1,4-triazole
ring (Figure 1). No unassignable peak is observed in this spec-
trum, indicating quantitative conversion of Cel–N3 to Cel–ꢀLac
with no side reaction.6
Figure 2. (a) Fluorescence spectral change of FITC–RCA120 on
addition of Cel–ꢀLac and (b) correlation between the fluores-
cence intensity and the concentration of Cel–ꢀLac: 20 ꢁC,
Ex = 490 nm, d ¼ 10 mm, Tris-HCl buffer (10 mM, pH 7.2),
[CaCl2] = 0.1 mM, [MnCl2] = 0.1 mM.
Cel–ꢀLac. It should be again noted that this specific interaction
arises from the introduced ꢀ-lactoside modules (Figure 2).
In conclusion, we established a simple synthetic route to-
ward 6-azide-6-deoxycellulose with perfect structural homoge-
neity along its main chain. The 6-azide-6-deoxycellulose can
act as key substrate on the subsequent click chemistry-based
introduction of functional modules onto the cellulose scaffold.
Although we focused herein the ꢀ-lactoside as the functional
module to develop cellulose-based glycoclusters, the introduced
functional modules should not be limited to such an oligosaccha-
ride. This assumption is reasonably supported by published data
showing that various functional modules (porphyrin, ferrocene,
pyrene, ammonium cation, etc.) can be readily introduced onto
curdlan through the same strategy. We believe that our strategy
is quite useful to develop cellulose-based eco-, bio-, and chiral
materials.
In contrast to native cellulose that is hardly soluble in water,
Cel–ꢀLac is well-soluble in water, and its lectin affinity can be
assessed based on the fluorescence titration assay using fluores-
cein isothiocyanate (FITC)-labeled lectins. Fluorescent intensity
of FITC–RCA120 (Ricinus communis agglutinin, ꢀ-Lac-specific)
was suppressed by addition of Cel–ꢀLac, and the dissociation
constant can be estimated by computational curve fitting to
1:46 ꢂ 10ꢃ7 M, indicating strong binding. On the other hand,
no such fluorescence spectral change was observed for FITC–
ConA (Concanavalin A, ꢁ-Glc/Man-specific). These fluorescent
spectroscopic data indicate strong and specific lectin affinity of
This work was partially supported by Grant-in-Aid for Sci-
entific Research (No. 18750103) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
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Figure 1. 13C NMR spectrum of Cel–ꢀLac: 300 MHz, DMSO-
d6, 60 ꢁC.
Supporting Information is available electronically on the CSJ-
Journal web site, http://www.csj.jp/journals/chem-lett/index.html.
Published on the web (Advance View) December 27, 2008; doi:10.1246/cl.2009.122