Cluster glycosides and heteroglycoclusters presented in alternative arrangements

Article abstract of DOI:10.1016/j.tetlet.2018.10.069

Multivalent carbohydrates, or glycoclusters, are useful tools to study glycan-lectin and glycan-enzyme recognition processes and have wide potential therapeutic applicability. Herein, we report the synthesis of novel glycoclusters presenting glucopyranose

Full text of DOI:10.1016/j.tetlet.2018.10.069

Accepted Manuscript
Cluster glycosides and heteroglycoclusters presented in alternative arrange-
ments
Andreza S. Figueredo, Luis O.B. Zamoner, Martin Rejzek, Robert A. Field,
Ivone Carvalho
PII:
S0040-4039(18)31310-8
https://doi.org/10.1016/j.tetlet.2018.10.069
TETL 50379
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 September 2018
24 October 2018
30 October 2018
Please cite this article as: Figueredo, A.S., Zamoner, L.O.B., Rejzek, M., Field, R.A., Carvalho, I., Cluster glycosides
and heteroglycoclusters presented in alternative arrangements, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.10.069
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Cluster glycosides and heteroglycoclusters presented in alternative arrangements
Andreza S. Figueredoa, Luis O. B. Zamoner,a Martin Rejzekb, Robert A. Fieldb, Ivone
Carvalhoa*
a School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café
s/n, Monte Alegre, Ribeirão Preto 14040-903, Brazil
b Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich
NR4 7UH, UK
*Corresponding author: carronal@usp.br (I. Carvalho); tel.: +551633154709; fax: +551633154879
ABSTRACT
Multivalent carbohydrates, or glycoclusters, are useful tools to study glycan-lectin and glycan-enzyme
recognition processes and have wide potential therapeutic applicability. Herein, we report the
synthesis of novel glycoclusters presenting glucopyranose units in alternate arrangements by coupling
through the C-1, C-2, C-3 or C-6 sugar positions and using tetra- and hexa-valent scaffolds for
multivalent display. Coupling the appropriate azide-functionalised D-glucopyranose units with
alkynlated penta- or dipenta-erythritol central cores was accomplished via copper-catalysed azide-
alkyne cycloaddition (CuAAC), yielding a panel of eight tetra- and hexa-valent glycoclusters in good
yields (52-83%). This click chemistry strategy was extended to the preparation of four
heteroglycoclusters using a tris(hydroxymethyl)-aminomethane (TRIS) central scaffold. One unit of
either the conventional 1-deoxy-D-nojirymicin iminosugar or its’ C-5 epimeric L-gulo isomer, were
incorporated along with three D-glucopyranose units linked through either C-1 or C-6.
Keywords: multivalency, glycoclusters, heteroglycoclusters, iminosugars, CuAAC click reaction.
1. Introduction
The multivalent nature of cell surface glycoconjugates underlies cellular interaction
processes with the extracellular matrix, microorganisms and other cells.1 Lectins, typically
multivalent carbohydrate-binding proteins, are particularly important in these events because
their sugar binding sites interact specifically with carbohydrate ligands. Therefore,
multivalent carbohydrate clusters with different architectures have been synthesised to
understand glycan clustering effects.2-4 Regardless of specific application, glycocluster
affinity and selectivity can be achieved by an appropriate balance between valency, topology
and the nature of both the carbohydrate and the linker that connects the latter to a central
scaffold.5,6.
In recent literature, several studies have reported the synthesis of multivalent
iminosugars, for instance based on deoxynojirimycin (DNJ 1), presented on various scaffolds,
such as dendrimers,7,8 cyclodextrins,9,10 fullerenes,11 tetravalent porphyrins,12 linear and
branched dextran,13 cyclo-peptoid clusters,14,15 calixarenes16 and self-assembled scaffolds
(biomimetic nanoparticles).17 In order to enhance their relative potency (rp) against glycoside
hydrolase enzymes, a trivalent DNJ conjugate 2 was constructed and showed a strong
multivalent effect (MVE) on jack bean α-mannosidase (JBman) (Fig. 1).7 In a similar sense,
heteroglycoclusters bearing more than one type of carbohydrate epitope have demonstrated

altered interactions between concanavalin A and α-mannopyranoside clusters containing
additional non-ligand sugars (β-D-glucopyranose or β-lactose) for this lectin.18 On a broader
front, aiming to hit multiple binding sites on lectins/glycosidases, a range of
pseudodisaccharide iminosugar and oligosaccharide glycosidase inhibitors, such as
MDL73945 3,19 acarbose 420,21 and triazole-iminosugar pseudodisaccharide 5,22 have been
investigated.
Figure 1. Chemical structures of glycosidase inhibitors including 1-deoxinojirimicin 1, a trivalent DNJ-based
glycocluster 2, pseudodisaccharide MDL-73945 3, acarbose 4 and triazole-iminosugar pseudodisaccharide 5.
Building on our previous work on multivalent glycans23-25 synthesised using CuAAC
click chemistry,26,27 we set out to explore new multivalent glycan assemblies based on
pentaerythritol and dipentaerythritol as molecular scaffolds, in order to access tetra- and hexa-
valent cluster glycosides. Furthermore, our intent was to explore systematic modification of
D-glucopyranoside units, by coupling through the sugar C-1, C-2, C-3 or C-6 positions.
Despite the plethora of complex multivalent lectin and glycosidase binding abilities described
above, to the best of our knowledge, only one example of glycoclusters bearing six copies of
glucose, trehalose, lactose or galactose presented on a dipentaerythritol scaffold has been
reported.28
2. Results and Discussion
2.1 Synthesis of cluster glycosides
Initially, symmetric pentaerythritol 6 containing four equivalent propargyl functional
groups was selected as the central scaffold for the synthesis of tetravalent cluster glycosides.

To this core, four Glc units were introduced in alternative orientations (coupled via the
glucose C-1, C-2, C-3 or C-6 positions). A similar approach was applied to hexa-propargyl
dipentaerythritol 7, to produce hexavalent glycoclusters (Scheme 1).
Scheme 1. New 1,2,3-triazole-based glycoclusters obtained from 1,3-dipolar cycloaddition reactions. Reagents
and conditions: i. Building blocks 6 or 7 (0.025 mmol), azidosugars 8-11 (1.1 eq. for each alkyne termination),
CuSO4 (0.05 eq.), Na ascorbate (0.1 eq.), DMF (0.1 mL), microwave heating at 80 °C, 15 min. (2x or 3x) ii.
NaOMe (1 M in methanol), MeOH (1 mL). 1.5 h, rt, then DOWEX® 50WX4-50.
The attachment of four propargyl groups on the pentaerythritol scaffold was achieved
with propargyl bromide in anhydrous DMF/KOH to afford the corresponding tetravalent core
6 in 38% yield (Scheme 1).29 Despite repeated attempts to prepare alkylated dipentaerythritol
7 using similar conditions, better results were obtained with the same alkylating reagent but
using phase-transfer catalysis conditions, according to previous reports (31% yield).30 The
azido-functionalised D-glucopyranoses modified at C-1, C-2, C-3 or C-6 (8-11), required for
subsequent CuAAC reactions, were prepared according to reported procedures, except for the
commercially available compound 8. Briefly, methyl 2-azido-2-deoxy-β-D-glucopyranoside 9
was obtained in three steps from D-glucosamine hydrochloride in 23% overall yield.31,32 The
synthesis of 3-azido-functionalised glucopyranose 10 started from commercially available
1,2:5,6-di-O-isopropylidene-α-D-allofuranose, which was initially converted into the
corresponding azide via a triflation/azide displacement sequence. Subsequent treatment of the

intermediate furanose diacetonide with aqueous trifluoroacetic acid followed by complete
acetylation of the crude product by treatment with acetic anhydride and pyridine produced the
pyranose acetate 10 as a mixture of anomers (α/β 4:1).33,34 Finallythe preparation of methyl 6-
azido-6-deoxy-β-D-glucopyranoside 11 was carried out following the modified method
described by Carvalho and co-workers,35 with formation of the methyl 6-O-tosyl-β-D-
glucopyranoside intermediate using a one-pot tosylation/acetylation reaction (43%). An
improved yield was achieved by performing this reaction at low temperature and with
dropwise addition of a solution of tosyl chloride in pyridine (68%). The synthesis was
completed by displacement of the 6-O-tosylate group with NaN3 in DMF, affording
azidosugar (11) in 77% yield.35,36
Next, the propargylated scaffolds 6 and 7 were coupled with azidosugars 8-11, via
copper-catalysed azide and alkyne cycloaddition (CuAAC) to give a panel of eight tetra- and
hexavalent protected glycoclusters (12-19) in good yields (52-83%) (Scheme 1). The reaction
was conducted on a small scale (0.025 mM of alkyne) with a 10 mol% excess of the
azidosugar to each alkyne and with copper sulfate/sodium ascorbate for in situ generation of
the Cu(I) catalyst.35 Typically, the coupling reactions were conducted in a sealed tube under
microwave-assisted conditions, with heating at 80 °C in DMF (0.1 mL), with the reaction
progress being monitored by TLC. After completion of the reaction, residual solvent was co-
evaporated with toluene and the crude product was purified by flash chromatography. The
1
structures of peracetylated 1,2,3-triazole-glycoclusters (12-19, Fig. 1) were confirmed by H
and 13C NMR spectroscopy, which showed the presence of a single 1,4-disubstituted
regioisomer and complete functionalization of the scaffold (four or six positions). Hydrogen
chemical shifts of the triazole-linked glucose were observed downfield compared to the
precursor azide 8-11 and the triazole hydrogen was observed in the range δ 7.6-8.1 ppm, with
integration of 4 H (12-15) or 6 H (16-19), while the triazole carbon not bonded to hydrogen
was detected at 144.9-146.0 ppm. Subsequently, O-deacetylation with NaOMe (1M in
methanol) afforded the deprotected glycoclusters 20-27 in near quantitative yield. Their
structures were confirmed by 1H NMR spectroscopy which showed absence of singlets for the
COCH3 groups. HRESI-MS analysis showed the characteristic adducts of [M+Na]+ or
[M+H]+ for compounds 20-27, although the hexavalent glycoclusters (24-27) were more ms-
sensitive and gave some in-source fragmentation during the analyses.
2.2 Synthesis of heteroglycoclusters
Using the same click chemistry approach described above, the synthesis of four
tetravalent heteroglycoclusters was conducted on a bifunctional dendrimer scaffold to enable

the presentation of two non-identical ligands in a 3:1 ratio37 (e.g. three glucopyranose units
and one DNJ-derived moiety), as outlined in Scheme 2. The synthesis of known dendrimer
scaffold 2838 was performed in two steps from commercially available
tris(hydroxymethyl)aminomethane (TRIS). The preparation of trivalent clusters connected at
glucopyranose C-1 (29) or C-6 (30) was carried out in a similar manner to glycoclusters 12-
19, using azidosugars 8 and 11, allowing the formation of peracetylated products 29 and 30 in
good (82%) and moderate yields (58%), respectively. Next, the introduction of azide
functionality on the cluster cores of 29 and 30, for further decoration with a second type of
carbohydrate ligand, was performed in two steps by quantitative removal of the Boc
protecting group with TFA to afford intermediates 31 and 32, which undergo a diazo-transfer
reaction with imidazole-1-sulfonyl azide39 and CuSO4 without further purification. The azide-
functionalized dendrimers 33 (78%) and 34 (61%) were obtained in good yields over two
steps. Their structures were confirmed by 1H NMR and 13C NMR spectroscopy, supported by
the appearance of a 2100 cm-1 IR stretch consistent with the presence of azido groups, which
was further substantiated by HRESI-MS analysis ([M+H]+ 1381.4605 for compound 33 and
[M+H]+ 1297.4700 for 34, respectively).

OR1
OR1
O
R1O
R1O
OR1
O
R1O
R1O
OAc
OR1
OAc
N
N
N
N
R1O
N
O
N
OR1
OR1
O
O
N
AcO
OAc
OR1
N
AcO
AcO
N3
N
N
N
R
O
N
OR1
O
OAc
OAc
O
35
37 R1=Ac
41 R1=H
O
O
R1O
N
N
v
8
N
N
O
N
R1O
N
N
OR1
N
N
OR1
N
R1O
R1O
N
OR1
OR1
OR1
OR1
O
O
iv
OR1
OR1
R1O
OR1
R1O
OR1
OR1
O
OR1
OR1
OAc
N
N
v
R1O
R1O
O
29 R=NHBoc, R1=Ac
31 R=NH2, R1=Ac
33 R=N3, R1=Ac
O
ii
NH
AcO
OAc
N
N
OR1
iii
O
O
O
N
OAc
OR1
N
N
N
36
O
i
O
O
38 R1=Ac
42 R1=H
R1O
N
N
O
N
N
N
28
OR1
N
OR1
R1O
R1O
R1O
OR1
OR1
R1O
R1O
OR1
O
OR1
OR1
R1O
OR1
OR1
N3
O
N
N
O
MeO
N
N
O
OAc
MeO
N
AcO
AcO
OMe
N
N
O
N
O
OAc
O
N
AcO
OAc
N
R
O
N
OR1
N
N
11
O
N
OAc
OR1
R1O
R1O
OR1
O
35
R1O
R1O
OR1
39 R1=Ac
43 R1=H
N
N
N
N
v
N
N
N
O
MeO
O
N N
MeO
O
R1O
R1O
O
OMe
R1O
R1O
iv
OMe
OR1
OR1
OAc
OR1
N
OR1
O
R1O
R1O
MeO
OR1
OR1
30 R=NHBoc, R1=Ac
32 R=NH2, R1=Ac
34 R=N3, R1=Ac
ii
iii
AcO
OAc
N
N
OAc
N
36
N
O
N
OR1
N
N
O
O
40 R1=Ac
44 R1=H
N
N
v
OR1
O
N
R1O
R1O
MeO
N
N
N
O
OMe
OR1
R1O
R1O
Scheme 2. Reagents and conditions: i. 28 (0.15 mmol), sugars 8 or 11 (1.1 eq. for each alkyne termination),
CuSO4 (0.03 eq.), Na ascorbate (0.1 eq.), DMF (0.1 mL), microwave heating at 80 °C, 15 min. (3x). ii. 29 or 30
(0.11 mmol), CH2Cl2/TFA 80% (2 mL, v/v), 2 h, rt. iii. CuSO4 (0.023 mmol), imidazole-1-sulfonyl azide
hydrosulfate (1.6 eq.), NaHCO3 (0.23 mmol), MeOH (4 mL). iv. Azide-functionalized dendrimer 33 or 34 (0.05
mmol), iminosugars 35 or 36 (0.05 mmol), CuSO4, (0.03 eq.), Na ascorbate (0.1 eq.), DMF (0.1 mL) microwave
heating at 80 °C, 15 min. (3x). v. NaOMe (1 M in methanol), MeOH (1 mL). 1.5 h, rt, then DOWEX® 50WX4-
50.
Finally, the preparation of heteroglycoclusters was achieved by the coupling of azide-
functionalized dendrimers 33 and 34 with N-propargylated iminosugars 3522 or 3640,41 under
the CuAAC conditions reported above. The four peracetylated glycoclusters 37-40 showed
1
13
characteristic H and C NMR signals related to two distinct types of sugars in a 3:1 ratio.
1
For instance, the H NMR spectrum of compound 37 exhibited two characteristic signals of
the triazole rings at δ 7.99 (3H, s) and δ 7.78 (1H, s) and a downfield shift was observed for
the central CH2 signal due to the influence of a new triazole ring, changing from δ 3.63
(compound 33) to δ 3.98 in glycocluster 37. The final deprotection step (NaOMe/MeOH)
afforded compounds 41-44 in quantitative yields. HRESI-MS analysis showed the
characteristic adducts of [M+H]+ for all these compounds (protected and deprotected

derivatives). Preliminary assessment of yeast α-glucosidase and almond β-glucosidase
inhibitory activities with heteroclusters 41-44 revealed that compounds 41 and 43 showed
some inhibition toward yeast α-glucosidase (IC50 225 and 210 μM) compared to DNJ as a
reference compound (110 μM). On the other hand, non-iminosugar glycoclusters 20-27
bearing four or six copies of D-glucopyranose attached to pentaerythritol or dipentaerythritol
scaffolds, including those linked by C-1 or C-6 sugar positions as observed in heteroclusters,
proved to be inactive against both yeast α-glucosidase and almond β-glucosidase at 1000 μM
concentration.
3. Conclusion
Using CuAAC click chemistry, four and six glucopyranose units were successfully
coupled to per-O-propargylated penta- and dipenta-erythritol scaffolds via the glucose C-1, C-
2, C-3 or C-6 positions, to produce multivalent glycoclusters presenting the carbohydrate in
alternative arrangements. CuAAC coupling was achieved under microwave-assisted
conditions, which allowed the ligation of sugar units to the central core through 1,2,3-triazole
linkers in good yields. Thus, a single unit of glycopyranose can afford structurally diverse
glycoclusters with defined spatial orientations for further use as tools to study essential
carbohydrate-protein interactions. The usefulness of this approach also enabled the
preparation of heteroclusters, bearing three glucopyranose units and one iminosugar attached
to a bifunctional dendrimer scaffold. These adducts partially resemble pseudooligosaccharides
and as such have potential as glycosidase inhibitors. The detailed biological evaluation of the
glycoclusters will be reported in due course.
Acknowledgements
We acknowledge financial support from Brazilian agencies: FAPESP (Fundação de Amparo à
Pesquisa do Estado de São Paulo-Brazil 2013/27038-8) and CNPQ (Conselho Nacional de
Desenvolvimento Científico e Tecnológico). Work in the UK was supported by the BBSRC
Institute Strategic Program on Understanding and Exploiting Metabolism (MET)
[BB/J004561/1] and the John Innes Foundation.
Supplementary data
The Supporting Information contains a description of the methods used and the structural
1
characterization of compounds including H and 13C NMR and two-dimensional spectra,

along ESI-MS analyses of the new intermediates and all products. Supplementary data
associated with this article can be found, in the online version, at:
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Cluster glycosides and heteroglycoclusters presented in alternative arrangements
Andreza S. Figueredoa, Luis O. B. Zamoner,a Martin Rejzekb, Robert A. Fieldb, Ivone Carvalhoa*

Highlights:
Tetra and hexavalent glycoclusters containing D-glucopyranose cores were synthesised
Sugars are linked in alternate arrangements through C-1, C-2, C-3 or C-6 positions
Heteroglycoclusters with non-identical ligands were also obtained
The iminosugar glycoclusters have trivalent D-glucose attached at C-1 or C-6 positions
These adducts have potential to resemble pseudooligosaccharides.