Syntheses of glycodendrimers having scyllo-inositol as the scaffold

Article abstract of DOI:10.1016/j.tetlet.2005.07.001

Synthetic glycoconjugated dendrimers have emerged as important functional glycomimetics for studying multivalency effects in the cell-cell communications. We report herein, a synthetic route to functionalized glycodendrimers with scyllo-inositol as the sc

Full text of DOI:10.1016/j.tetlet.2005.07.001

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6063–6066
Syntheses of glycodendrimers having scyllo-inositol as the scaffold
Nan-Young Lee, Woo-Jae Jang, Seok-Ho Yu, Jungkyun Im and Sung-Kee Chung*
Department of Chemistry, Division of Molecular and Life Sciences, Pohang University of Science and Technology,
Pohang 790-784, Korea
Received 11 June 2005; revised 30 June 2005; accepted 1 July 2005
Available online 15July 2005
Abstract—Synthetic glycoconjugated dendrimers have emerged as important functional glycomimetics for studying multivalency
effects in the cell–cell communications. We report herein, a synthetic route to functionalized glycodendrimers with scyllo-inositol
as the scaffold, which have a directed geometry; one side of the dendrimers is designed for ready attachment to the AFM probe/
solid matrix, and the other to have a varying number of a sugar.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Glycobiology is undergoing a kind of renaissance in the
post-genomic era, since there are a number of important
biological and physiological phenomena that depend on
the carbohydrate–protein interactions.1 One of the
major topics in the current glycobiology research is
understanding the precise nature of the carbohydrate–
protein interactions, which play crucial roles in cell–cell
communications. The binding affinity of the glycan-
binding proteins (GBP) for individual monosaccharide
units is generally very weak. However, the binding
affinity increases synergistically with an increasing
number of sugar residues (Ôglycoside cluster effectÕ).2 A
strong glycocluster effect, a result of multivalent interac-
tions, obviously requires a sugar-cluster structure that
can present the sugars with proper orientation and
spacing. In order to mimic this synergy effect and their
biological functions a variety of glycodendrimers have
been developed.3
ble of measuring such interactions in the pico-Newton
range under pseudo-physiological conditions, and it
has emerged as a useful tool for probing the interaction
force between individual ligand–receptor complexes.4
With such a goal in mind (e.g., measuring the unbinding
force between concanavalin A and a-mannosyl sugar res-
idues), we have developed synthetic routes to various glyco-
dendrimers in which the 3D-geometry is well defined
and better controlled. As the first example of such glyco-
dendrimers, we wish to report herein a synthetic route to
functionalized glycodendrimers based on the scyllo-ino-
sitol scaffold, in which the directionality as well as the
number and density of the terminal carbohydrate may
be controlled for their appropriate applications.
It is envisioned that the overall linear directionality of
the desired glycodendrimer structure can be introduced
by tying up the alternating hydroxyl groups of readily
available myo-inositol in the form of orthoformate5
and the following stereo-inversion of the equatorial
hydroxyl group as shown in Scheme 1. Thus, after
protecting the equatorial hydroxyl group in the myo-
inositol orthoformate 1 as tert-butyldimethylsilyl ether
(2),5a allylation of the two remaining hydroxyl groups
and subsequent removal of the TBDMS protecting
group gave compound 4.5e Now the equatorial hydroxyl
group of 4 was efficiently inverted to the axial orienta-
tion by oxidation with PCC in dichloromethane and
subsequent reduction with NaBH4 in methanol/THF.
Additional allylation of compound 6 followed by the
hydrolysis of the orthoformate in compound 75f
provided the tri-hydroxy compound (8). Reaction
between 8 and trimethyl 4-bromoorthobutyrate in
In order to assess the carbohydrate–protein interactions
more precisely, it would be highly desirable to be able to
control the carbohydrate density and the size of glyco-
clusters. Furthermore, a direct measurement of the
binding interactions at the individual molecular level
would provide more accurate information needed for
the fundamental insights and potential applications.
The atomic force microscopy (AFM) is in principle capa-
Keywords: Glycomics; Glycoside cluster effect; Glycodendrimer; scyllo-
Inositol; PAMAM.
*
Corresponding author. Tel.: +82 54 279 2103; fax: +82 54 279
3399; e-mail: skchung@postech.ac.kr
0040-4039/$ - see front matter ꢀ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.001

6064
N.-Y. Lee et al. / Tetrahedron Letters 46 (2005) 6063–6066
OH
O
O
O
O
HO
HO
OH
OH
O
O
e
c
a
R1O
d
R1O
b
O
OH
OH
O
OH
1 R1 = H
2 R1 = TBDMS
3 R1 = TBDMS
4 R1 = H
myo-inositol
O
O
O
O
O
O
O
O
g
h
O
f
O
O
O
O
OH
O
O
O
O
5
6
7
R2
R2
OH
O
O
O
O
O
O
O
i
m
O
HO
OH
O
O
O
O
O
O
O
R
3 R3
R3
9
R2 = Br
13 R2 = NHBoc, R3 = OH
14 R2 = NHBoc, R3 = Br
15 R2 = NHBoc, R3 = N3
16 R2 = NHBoc, R3 = NH2
j
n
o
p
8
10 R2 = N3
11 R2 = NH2
12 R2 = NHBoc
k
l
Scheme 1. Reagents and conditions: (a) (MeO)3CH, TSA, DMF, 110 ꢁC, 72%; (b) TBDMSCl, imidazole, DMF, 0 ꢁC ! rt, 75%; (c) allyl bromide,
NaH, DMF, 81%; (d) TBAI, THF, quant.; (e) PCC, CH2Cl2, reflux, 79%; (f) NaBH4, MeOH/THF, quant.; (g) allyl bromide, NaH, DMF, 94%; (h)
TSA, MeOH/EtOAc, quant.; (i) trimethyl 4-bromoorthobutyrate, TSA, toluene, 100 ꢁC, 78%; (j) NaN3, DMF, 93%; (k) PPh3, H2O, THF, 93%; (l)
(Boc)2O, TEA, THF, 87%; (m) 9-BBN, THF, 3 N NaOH, H2O2, 82%; (n) PPh3, CBr4, THF, 87%; (o) NaN3, DMF, quant.; (p) H2, Pd–C, THF.
toluene containing a catalytic amount of p-toluene
sulfonic acid with removal of azeotropic water5b gave
the bidirectional key intermediate (9),6 in which the
two functional groups could now be independently
and orthogonally manipulated.
sequence successfully resulted in the doubling of peri-
pheral amino functionalities in g2-dendrimer 18; thus
doubling of branched chain numbers could be accom-
plished with each increasing generation.
Secondly, the thiourea coupling method has been suc-
cessfully utilized for the preparation of glycoconjugated
dendrimers.11 Thus, each of the amino-functionalized
dendrimers (16–18) was reacted with 2,3,4,6-tetra-O-
acetyl-a-D-mannosyl isothiocyanate11 to produce the
thiourea-linked a-mannosylated dendrimers 19, 20,
and 21 in 54%, 55%, and 26% yields, respectively. After
removal of the Boc protecting group from the amino
functionality in the glycodendrimers (19–21),12 the
resulting products should be suitable for the attachment
to the AFM probe or other solid matrix.
First, the conversion of bromide 9 to azide 10 was
effected by treatment with sodium azide in DMF, and
the azide (10) was reduced with triphenylphosphine in
THF in the presence of water to give the primary amine
11.7 After the amino group protection of 11 with Boc2O
and triethylamine, the product (12) was hydroborated
with 9-BBN and oxidatively worked up to generate com-
pound 13. The alcohol functionality of 13 was conve-
niently converted to the amino functionality (16)8 by
successive Appel procedure9 to a bromide (14), conver-
sion to an azide (15), and its hydrogenolysis over Pd–
C in THF. The scaffold molecule (16) is now ready for
glycosylation as well as chain elongation and multiplica-
tion to the desired dendrimeric structures (Scheme 2).
First, exhaustive Michael addition of the amine func-
tionality with methyl acrylate in methanol in dark and
the subsequent amidation of the resulting esters with
ethylenediamine10 afforded amidoamine dendrimer 17
(g1) in 80% yield. Reiteration of this two-step reaction
In summary, we have successfully utilized the scyllo-ino-
sitol scaffold in developing a synthetic methodology for
functional glycodendrimers having a linear bi-direction-
ality as well as a varying number of terminal sugars,
which are suitable for the glycobiology application stud-
ies such as multivalent glycomimetics and construction
of carbohydrate microarrays after suitable functional
group modifications and structural elaborations.

N.-Y. Lee et al. / Tetrahedron Letters 46 (2005) 6063–6066
6065
NHBoc
NHBoc
O
O
O
O
O
b
O
O
O
O
O
O
O
O
N
N
N
O
O
NH
O
O
NH
O
NHR
NH
NH
NH
NHR
NHR
O
NH
RHN
RHN
NHR
RHN
NHR
RHN
OAc
OAc
16 R = H
19 R =
a
OAc
HN
S
17 R = H
20 R =
a
HN
O
OAc
OAc
S
AcO
OAc
AcO
NHBoc
O
O
O
O
O
N
O
N
N
O
b
O
HN
O
O
NH
NH
O
O
NH
NH
NH
O
N
O
N
N
O
NH
N
O
N
N
NH
O
O
RHN
RHN
NH
O
NH
NH
O
NH
O
O
NH
O
NH
O
NH
NHR
NH
NH
NH
RHN
NHR
RHN
NHR
RHN
NHR
RHN
NHR
NHR
OAc
18 R = H
21 R =
a
HN
O
OAc
OAc
S
AcO
Scheme 2. Reagents and conditions: (a) 2,3,4,6-tetra-O-acetyl-a-D-mannosyl isothiocyanate, CH2Cl2, reflux, 54% (19), 55% (20), 26% (21); (b) (i)
methyl acrylate, MeOH, in dark, (ii) ethylene diamine, MeOH, 80% (17), 47% (18).
Acknowledgements
References and notes
1. (a) Dwek, R. A.; Butters, T. D. Chem. Rev. 2002, 102; (b)
Hurtley, S.; Service, R.; Szuromi, P. Science 2001, 291,
2337; (c) Maeder, T. Sci. Am. 2002, 40–47.
2. (a) Fukuda, M. Bioorg. Med. Chem. 1995, 3, 207–215; (b)
Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 26, 321–327;
(c) Mammen, M.; Choi, S. K.; Whitesides, G. M. Angew.
Chem., Int. Ed. 1998, 37, 2754–2794; (d) Lee, R. T.; Lee,
Y. C. Glycoconjugate J. 2000, 17, 543–551; (e) Lundquist,
J. J.; Toone, E. J. Chem. Rev 2002, 102, 555–578.
We gratefully acknowledge the financial supports
received from POSTECH (BSRI fund-2004), POSCO
(Technology Development Grant), and KISTEP (Glyco-
biology Program 2004-02087).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2005.
07.001.
3. (a) Dubber, M.; Lindhorst, T. K. J. Org. Chem. 2000, 65,
5275–5281; (b) Woller, E. K.; Cloninger, M. J. Org. Lett.

6066
N.-Y. Lee et al. / Tetrahedron Letters 46 (2005) 6063–6066
2002, 4, 7–10; (c) Ko¨hn, M.; Benito, J. M.; Ortiz-Mellet,
AOCH2CH@CHcisHtrans), 5.91 (ddt, J = 17.2, 10.5,
5.5 Hz, 3H, 3 · AOCH2CH@CHcisHtrans); 13C NMR
(CDCl3): d 27.3, 34.1, 35.8, 69.3, 71.1, 72.6, 110.0, 117.8,
135.2; MS (FAB) m/z 453 [M+Na]+; HRMS (FAB) m/z
calcd for C19H28BrO6: 431.1069. Found: 431.1068 [M+1]+.
7. Mukai, C.; Sugimoto, Y.; Miyazawa, K.; Yamaguchi, S.;
Hanaoka, M. J. Org. Chem. 1998, 63, 6281–6287.
C.; Lindhorst, T. K. ChemBioChem 2004, 5, 771–777; (d)
Li, Y.; Zhang, X.; Chu, S.; Yu, K.; Guan, H. Carbohydr.
Res. 2004, 339, 873–879; (e) Bovin, N. V.; Gabius, H.-J.
Chem. Soc. Rev. 1995, 413–421; (f) Kitov, P. I.; Sadowska,
J. M.; Mulvey, G.; Armstrong, G. D.; Ling, H.; Pannu, N.
S.; Read, R. J.; Bundle, D. R. Nature 2000, 403, 669–672;
(g) Fan, E.; Zhang, Z.; Minke, W. E.; Hou, Z.; Verlinde,
C. L. M. J.; Hol, W. G. J. J. Am. Chem. Soc. 2000, 122,
8. Compound (16): 1H NMR (CD3OD): d 1.43 (s, 9H), 1.57–
1.85(m, 4H), 1.77 (p, J = 6.25Hz, 6H), 2.81 (t, J =
6.46 Hz, 6H), 2.98 (m, 2H), 3.71 (t, J = 6.0 Hz, 3H), 4.1 (s,
3H), 4.43 (s, 3H); 13C NMR (CD3OD): d 24.9, 28.9, 32.0,
35.3, 40.2, 41.5, 69.6, 70.4, 75.1, 79.9, 111.1, 158.6; MS
(FAB) m/z 519 [M+1]+; HRMS (FAB) m/z calcd for
C24H47N4O8: 519.3394. Found: 519.3389 [M+1]+.
9. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801–811.
10. Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III
Angew. Chem., Int. Ed. Engl. 1990, 29, 138–175.
11. (a) Lindhorst, T. K.; Kieburg, C. Synthesis 1995, 1228–
1230; (b) Lindhorst, T. K.; Kieburg, C. Angew. Chem., Int.
Ed. 1996, 35, 1953–1956.
12. The Boc protecting group could be selectively removed.
For example, treatment of compound 19 with TMSCl,
NaI, MeOH, and TEA in CH3CN gave the Boc depro-
tected compound in 88% yield without causing hydrolysis
of the orthoester which is labile to usual acidic Boc
deprotection conditions. It is envisioned that the glyco-
dendrimer after removal of the acetate groups in sugar,
can be reacted to a SAM on AFM tip containing
N-hydroxysuccinimide-activated carboxy terminal groups,
which is expected to preferentially react with NH2 group
over OH groups.
´
2663–2664; (h) Andre, S.; Pieters, R. J.; Vrasidas, I.;
Kaltner, H.; Kuwabara, I.; Liu, F.-T.; Liskamp, R. M. J.;
Gabius, H.-J. ChemBioChem 2001, 2, 822–830.
4. (a) Lo, Y.-S.; Zhu, Y.-J.; Beebe, T. P. Langmuir 2001, 17,
3741–3748; (b) Touhami, A.; Hoffmann, B.; Vasella, A.;
Denis, F. A.; Dufreˆne, Y. F. Langmuir 2003, 19, 1745–
1751.
5. (a) Lee, H. W.; Kishi, Y. J. Org. Chem. 1985, 50, 4402–
4404; (b) Tse, B.; Kishi, Y. J. Am. Chem. Soc. 1993, 115,
7892–7893; (c) Baudin, G.; Gla¨nzer, B. I.; Swaminathan,
K. S.; Vasella, A. Helv. Chim. Acta 1988, 71, 1367–1378;
(d) Chung, S. K.; Kwon, Y. U.; Chang, Y. T.; Sohn, K.
H.; Shin, J. H.; Park, K. H.; Hong, B. J.; Chung, I. H.
Bioorg. Med. Chem. 1999, 7, 2577–2589; (e) Devaraj, S.;
Shashidar, M. S.; Dixit, S. S. Tetrahedron 2005, 61, 529–
536; (f) Kishi, Y.; Tse, B.; U.S. Patent 5 412 080, 1995.
6. Compound (9): 1H NMR (CDCl3): d 1.80 (dd, J = 8.4,
6.5Hz, 2H), 2.0 (m, 2H), 3.41 (t, J = 6.7 Hz, 2H), 4.11 (dt,
J = 5.5, 1.4 Hz, 6H, 3 · AOCH2CH@CH2), 4.16 (dd,
J = 4.5, 2.8 Hz, 3H), 4.39 (dd, J = 4.4, 2.9 Hz, 3H), 5.18
(ddt, J = 10.3, 1.6, 1.2 Hz, 3H, 3 · AOCH2CH@
CHcisHtrans), 5.31 (ddt, J = 17.2, 1.7, 1.6 Hz, 3H, 3 ·