Synthetic studies on dendritic glycoclusters: A convergent palladium-catalyzed strategy

Article abstract of DOI:10.1016/S0008-6215(01)00085-4

A facile Pd-catalyzed strategy by which multiantennary glycoclusters and sugar dendrons can be readily assembled in one-step is described.

Full text of DOI:10.1016/S0008-6215(01)00085-4

www.elsevier.nl/locate/carres
Carbohydrate Research 332 (2001) 215–219
Note
Synthetic studies on dendritic glycoclusters: a convergent
palladium-catalyzed strategy
Saumitra Sengupta,* Subir Kumar Sadhukhan
Department of Chemistry, Jada6pur Uni6ersity, Calcutta 700 032, India
Received 8 January 2001; accepted 21 March 2001
Abstract
A facile Pd-catalyzed strategy by which multiantennary glycoclusters and sugar dendrons can be readily assembled
in one-step is described. © 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Glycoclusters; Propargyl glycosides; Sugar acrylates; Pd-catalyzed reactions
ties. In view of these, in recent years, much
attention has been paid towards synthesis of
multivalent dendritic glycoclusters (glycoden-
drimers).4 Since dendrimer synthesis requires
multiple coupling reactions to be carried out
in one step, Pd-catalyzed reactions, in view of
their high atom efficiencies, appeared ideally
suited for this purpose. We now present here a
facile synthetic strategy by which multianten-
nary glycoclusters can be rapidly assembled in
a convergent way using the Pd-catalyzed reac-
tions, our disclosure being prompted by a
recent report on the synthesis of some carbo-
hydrate dimers using the Sonogashira-type
coupling reactions.5
Carbohydrate–protein interactions are re-
sponsible for several cell–cell and host–
pathogen interactions.1 These interactions,
however, are very weak and hence, as a com-
pensatory measure, nature adopts the multiple
binding strategy. Thus, in many biological
phenomena, carbohydrates and their recogni-
tion domains are organized as supramolecular
clusters that are held together by co-operative
binding forces.2 However, little is known on
the nature of these forces, a detailed under-
standing of which may lead to effective de-
signs of glycoprotein inhibitors and other
carbohydrate-based therapeutic agents.2,3
Dendritic glycoclusters can play a major role
towards these ends. Dendrimers having pe-
ripheral saccharide units can be constructed in
varying shapes, sizes and carbohydrate con-
tent, and their binding studies with proteins
may provide insight into the topography of
the binding sites and their directional proper-
In this study, we have used the readily
available
D
-glucose-derived b-propargyl gly-
coside (1)6 as the antennary saccharide ligand.
A threefold Pd-catalyzed reaction of 1 with
1,3,5-tribromobenzene (2) under a Sono-
gashira-coupling protocol without the use of
CuI (Pd(dba)2, 4PPh3, Et3N, DMF, 60 °C)
smoothly gave rise to the centrally planar
triantennary glycocluster 3 in 70% isolated
yield after silica-gel chromatography (Scheme
* Corresponding author. Fax: +91-33-4734266.
E-mail address: jusaumitra@yahoo.co.uk (S. Sengupta).
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00085-4

216
S. Sengupta, S.K. Sadhukhan / Carbohydrate Research 332 (2001) 215–219
1). This coupling reaction was best carried out
in the absence of CuI, a co-catalyst routinely
used in Pd-catalyzed coupling reactions of ter-
minal acetylenes, which otherwise led to con-
siderable dimerization5a of the propargyl
glycoside 1, resulting in complex product mix-
tures. The glycocluster 3 was produced with
complete retention of the starting b-saccharide
configuration (l 4.82, J1,2 7.8 Hz in 3), attest-
ing to the mild and neutral conditions em-
ployed for its synthesis.
Scheme 2. (i) MeOH, concd H2SO4; (ii) LiAlH4, THF 0 °C;
(iii) 10% Pd(dba)2, 40% PPh3, DMF, Et3N, 60 °C; (iv) propar-
gyl bromide, NaH, THF.
Heck olefin component (Scheme 3). A four-
fold Heck reaction of 10 with the centrally
tetrahedral tetratopic core tetra(p-iodo-
phenyl)methane (11)7 under Jefferey’s phase-
transfer catalyzed conditions (Pd(OAc)2,
Bu4NBr, NaHCO3, DMF, 80 °C) then
smoothly gave rise to the topologically inter-
esting three-dimensional glycocluster 12 in
60% isolated yield.
In summary, we have shown a facile Pd-cat-
alyzed strategy by which multivalent glyco-
clusters and sugar dendrons can be rapidly
assembled in one step. The methodology is
particularly attractive since it can lead to rigid
and yet topologically different multivalent gly-
coclusters through appropriate choice of the
aromatic cores (cf. 3 vs. 12). Based on this
strategy, synthesis of higher generation glyco-
clusters is currently in progress.
Scheme 1. (i) 10% Pd(dba)2, 40% PPh3, DMF, Et3N, 60–
70 °C.
We then turned our attention towards syn-
thesis of an appropriate dendron for the con-
vergent assembly of higher generation
glycoclusters. Thus, 3,5-diiodobenzoic acid (4)
was first converted to the corresponding ben-
zyl alcohol 6 through conventional esterifica-
tion, followed by LiAlH4 reduction (Scheme
2). A twofold Pd-catalyzed coupling of 6 with
1, under the same copper-less coupling condi-
tions described above, gave rise to the di-
antennary benzyl alcohol 7 in 45% yield. It
was then converted to the propargyl ether
dendron 8 (75%), which may be used for
coupling with the tritopic core 2 to produce a
second-generation glycocluster.
1. Experimental
General methods.—All melting points are
uncorrected. IR spectra were taken in a
Perkin–Elmer R-297 spectrometer. NMR
spectra were recorded in CDCl3 solutions on a
Bruker Avance-300 (300 MHz) instrument
and are reported in the l scale, ppm downfield
from tetramethylsilane as the internal stan-
dard. Optical rotations were measured on a
JASCO DIP-360 automatic polarimeter. Ele-
mental analyses were carried out at the Indian
We also present here an example by which
multivalent glycoclusters can be rapidly as-
sembled via a multiple Heck reaction strategy.
For this purpose, we have used the saccharide
acrylate ester 10, derived from 1,2:5,6-di-O-
isopropylidene-a- -glucofuranose (9), as the
D

S. Sengupta, S.K. Sadhukhan / Carbohydrate Research 332 (2001) 215–219
217
Association for the Cultivation of Science.
The b-propargyl glycoside 1,6, 3,5-diiodoben-
zyl alcohol (6),8 3-O-acryloyl-1,2,5,6-di-O-iso-
was evaporated under reduced pressure. The
residue was purified by preparative TLC on
silica gel (3:2 EtOAc–petroleum ether) to give
3 (0.06 g, 70%): mp 108–110 °C; [h]2D0 −38.2°
(c 1.1, CHCl3). IR: 3010, 1750, 1360, 1210,
propylidene-a-
D
-glucofuranose
(10)9
and
tetra(4-iodophenyl)methane (11)7 were pre-
pared following the cited literature proce-
dures. All reactions were carried out using
dried distilled solvents under a N2 atmo-
sphere. The Pd-catalyzed coupling reactions
were carried out in solutions that were de-
gassed thoroughly with N2. Reactions were
monitored by thin-layer chromatography
(TLC) on glass plates precoated with Silica
Gel G (Tara Chemicals). Components were
visualized by staining with iodine or heating
on a hot plate after spraying with aq H2SO4.
Petroleum ether refers to the fraction boiling
at 60–80 °C range.
1
1035 cm−1. H NMR: l 2.01 (s, 9 H), 2.03 (s,
9 H), 2.05 (s, 9 H), 2.09 (s, 9 H), 3.76 (ddd, 3
H, J 9.3, 4.3, 2.4 Hz), 4.17 (dd, 3 H, J 12.3,
2.1 Hz), 4.29 (dd, 3 H, J 12.3, 4.5 Hz), 4.59 (s,
6 H), 4.82 (d, 3 H, J 7.8 Hz), 5.04 (dd, 3 H, J
9.3, 8.1 Hz), 5.09–5.15 (m, 3 H), 5.23–5.29
(m, 3 H), 7.47 (s, 3 H). Anal. Calcd for
C57H66O30: C, 55.64; H, 5.36. Found: C, 56.14;
H, 5.02.
3,5-Bis[1%-O-(2%%,3%%,4%%,6%%-tetra-O-acetyl-i-
-glucofuranosyl)prop-3%-ynyl]benzyl alcohol
D
(7).—Pd(dba)2 (8 mg, 0.013 mmol) was added
to a degassed solution of 3,5-diiodo benzyl
alcohol (6) (0.024 g, 0.066 mmol), the propar-
gyl glycoside 1 (0.08 g, 0.2 mmol) and PPh3
(0.01 g, 0.04 mmol) in a mixture of DMF (2
mL) and Et3N (2 mL). The mixture was
heated at 60 °C for 30 h. It was then concen-
trated under reduced pressure, diluted with
water and extracted with CH2Cl2 (3×5 mL).
The organic layer was dried over Na2SO4, and
the solvent was evaporated under reduced
pressure. The residue was purified by prepara-
tive TLC over silica gel (70:30 EtOAc–
petroleum ether) to give 7 (0.027 g, 45%): [h]D20
1,3,5-Tri[1%-O-(2%%,3%%,4%%,6%%-tetra-O-acetyl-
i- -glucofuranosyl)prop-3%-ynyl]benzene (3).—
D
Pd(dba)2 (6 mg, 0.01 mmol) was added to a
degassed solution of 1,3,5-tribromobenzene
(2) (0.02 g, 0.067 mmol), the propargyl gly-
coside 1 (0.121 g, 0.301 mmol) and PPh3 (0.01
g, 0.04 mmol) in a mixture of DMF (2 mL)
and Et3N (2 mL). The mixture was heated at
70 °C for 30 h. It was then concentrated under
reduced pressure, diluted with water and ex-
tracted with CH2Cl2 (3×5 mL). The organic
layer was dried over Na2SO4, and the solvent
Scheme 3. (i) CH2ꢀCHCOCl, Et3N, cat. DMAP, CH2Cl2, 0 °C–rt; (ii) 40% Pd(OAc)2, Bu4NBr, NaHCO3, DMF, 80° C.

218
S. Sengupta, S.K. Sadhukhan / Carbohydrate Research 332 (2001) 215–219
residue was purified by preparative TLC on
silica gel (60:40 petroleum ether–EtOAc) to
give 12 (0.014 g, 60%): mp 212–214 °C; [h]D20
−42.3° (c 1.2, CHCl3). IR: 2980, 1710, 1630,
−26.1° (c 1, CHCl3). IR: 3010, 1755, 1365,
1
1215, 1035 cm−1; H NMR: l 2.01 (s, 6 H),
2.03 (s, 6 H), 2.05 (s, 6 H), 2.08 (s, 6 H),
3.73–3.80 (m, 2 H), 4.17 (dd, 2 H, J 12.3, 2.1
Hz), 4.29 (dd, 2 H, J 12.3, 4.5 Hz), 4.59 (s, 4
H), 4.69 (s, 2 H), 4.83 (d, 2 H, J 7.9 Hz), 5.04
(t, 2 H, J 9.3 Hz), 5.12 (t, 2 H, J 9.6 Hz), 5.26
(t, 2 H, J 9.3 Hz), 7.43 (s, 3 H). Anal. Calcd
for C41H46O21: C, 56.32; H, 5.26. Found: C,
55.89; H, 5.11.
1
1200, 1150, 1060, 1015 cm−1. H NMR: l
1.30 (s, 12 H), 1.31 (s, 12 H), 1.41(s, 12 H),
1.54 (s, 12 H), 4.07 (br s, 8 H), 4.28 (br s, 8
H), 4.56 (d, 4 H, J 3.5 Hz), 5.39 (br s, 4 H),
5.91 (d, 4 H, J 3.5 Hz), 6.40 (d, 4 H, J 15.9
Hz), 7.25 (d, 8 H, J 8.2 Hz), 7.45 (d, 8 H, J 8.2
Hz), 7.68 (d, 4 H, J 15.9 Hz). Anal. Calcd for
C85H100O28: C, 65.05; H, 6.41. Found: C,
64.87; H, 6.15.
3,5-Bis[1%-O-(2%%,3%%,4%%,6%%-tetra-O-acetyl-i-
- glucofuranosyl)prop - 3% - ynyl]benzylprop - 2-
D
yn-1-ol (8).—NaH (50% dispersion in mineral
oil, 4 mg, 0.08 mmol) was added to a stirred
solution of 7 (0.05 g, 0.055 mmol) in THF (2
mL) at 0 °C. After 15 min, a solution of
propargyl bromide (0.014 g, 0.11 mmol) in
THF (1 mL) was added. The reaction mixture
was stirred at ambient temperature for 24 h. It
was then diluted with CH2Cl2 (5 mL) and
washed with water, and the organic layer was
dried over Na2SO4. Evaporation of solvent
under reduced pressure, followed by prepara-
tive TLC on silica gel (60:40 EtOAc–
petroleum ether), gave 8 (0.038 g, 75%): mp
65–66 °C; [h]2D0 −20.7° (c 1.2, CHCl3). IR:
Acknowledgements
S.K.S. thanks CSIR, New Delhi for a senior
research fellowship.
References
1. Dwek, R. A. Chem. Re6. 1996, 96, 683–720.
2. (a) Lee, Y. C.; Lee, R. T. Neoglycoconjugates: Preparation
and Applications; Academic: San Diego, 1994;
(b) Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28,
321–327;
(c) Mammen, M.; Choi, S. K.; Whitesides, G. M. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2754–2794.
3. Toyokuni, T.; Singhal, A. K. Chem. Soc. Re6. 1995, 24,
231–242.
1
2890, 1750, 1365, 1220, 1040 cm−1. H NMR:
l 2.01 (s, 3 H), 2.03 (s, 3 H), 2.05 (s, 3 H),
2.08 (s, 3 H), 2.09 (s, 3 H), 2.10 (s, 3 H), 2.12
(s, 3 H), 2.13 (s, 3 H), 3.66–3.71 (m, 1 H),
3.74–3.79 (m, 1 H), 3.84 (t, 1 H, J 9.2 Hz),
4.10–4.33 (m, 6 H), 4.57 (s, 2 H), 4.59 (s, 2
H), 4.74 (d, 1 H, J 7.9 Hz), 4.82 (d, 1 H, J 7.9
Hz), 4.90–5.20 (m, 7 H), 5.26 (t, 1 H, J 9.3
Hz), 7.40 (s, 2 H), 7.45 (s, 1 H). Anal. Calcd
for C44H48O21: C, 57.92; H, 5.26. Found: C,
57.66; H, 5.04.
4. (a) Reviews: Roy, R. Top. Curr. Chem. 1997, 187, 241–
274;
(b) Jayaraman, N.; Nepogodiev, S. A.; Stoddart, J. F.
Chem. Eur. J. 1997, 3, 1193–1199;
(c) Recent syntheses: Sliedregt, L. A. J. M.; Rensen, P. C.
N.; Rump, E. T.; van Santbrink, P. J.; Bijsterbosch, M.
K.; Valentijn, A. R. P. M.; van der Marel, G. A.; van
Boom, J. H.; van Berkel, T. J. C.; Biessen, E. A. L. J.
Med. Chem. 1999, 42, 609–618;
(d) Dimick, S. D.; Powell, S. C.; McMahon, S. A.;
Moothoo, D. N.; Naismith, J. H.; Toone, E. J. J. Am.
Chem. Soc. 1999, 121, 10286–10296;
(e) Jiao, H.; Hindsgaul, O. J. Carbohydr. Chem. 1999, 18,
499–513;
(f) Fulton, D.; Stoddart, J. F. Org. Lett. 2000, 2, 1113–
1116;
(g) Sadalapure, K.; Lindhorst, T. K. Angew. Chem., Int.
Ed. Engl. 2000, 39, 2010–2013;
(h) Dubber, M.; Lindhorst, T. K. J. Org. Chem. 2000, 65,
5275–5281;
Tetra[4-(1%,2%,5%,6%-di-O-isopropylidene-h- -
D
glucofuran-3-oxycarbonylethenyl)phenyl] meth-
ane (12).—Pd(OAc)2 (1.0 mg, 0.004 mmol)
was added to a degassed solution of tetra(4-
iodophenyl)methane (11) (0.012 g, 0.014
mmol), the sugar acrylate 10 (0.028 g, 0.087
mmol), KOAc (0.014 g, 0.145 mmol) and
Bu4NBr (0.02 g, 0.058 mmol) in DMF (3 mL).
The reaction mixture was heated at 80 °C for
12 h. It was then concentrated under reduced
pressure, diluted with water, and extracted
with CH2Cl2 (3×5 mL). The organic layer
was dried over Na2SO4, and the solvent was
evaporated under reduced pressure. The
(i) Lindhorst, T. K.; Dubber, M.; Krallmann-Wenzel, U.;
Ehlers, S. Eur. J. Org. Chem. 2000, 2037–2034.
5. (a) Roy, R.; Das, S. K.; Santoyo-Gonzalez, F.; Hernan-
dez-Mateo, F.; Dam, T. K.; Brewer, C. F. Chem. Eur. J.
2000, 6, 1757–1762;
(b) de Kort, M.; Correa, V.; Valentijn, A. R. P. M.; van
der Marel, G. A.; Potter, B. V. L.; Taylor, C. W.; van
Boom, J. H. J. Med. Chem. 2000, 43, 3295–3303.
6. Mereyala, H. B.; Gurrala, S. R. Carbohydr. Res. 1998, 307,
351–354.

S. Sengupta, S.K. Sadhukhan / Carbohydrate Research 332 (2001) 215–219
219
7. (a) Menger, F. M.; Su, D. Tetrahedron Lett. 1997, 38,
1485–1488;
8. Zeng, F.; Zimmerman, S. C. J. Am. Chem. Soc. 1996, 118,
5326–5327.
9. Kunz, H.; Mu¨ller, B.; Schanzenbach, D. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 267–269.
(b) Sengupta, S.; Sadhukhan, S. K. Tetrahedron Lett.
1998, 39, 1237–1238.
.