Synthesis of a small library of bivalent α-d-mannopyranosides for lectin cross-linking

Article abstract of DOI:10.1016/j.carres.2011.03.041

A small library of bivalent α-d-mannopyranosides having rigid linkers was constructed in order to evaluate the effects of inter-saccharide distances upon multivalent binding interactions with plant and bacterial lectins. To this end, iodoaryl and propargyl α-d-mannopyranosides were synthesized and the former treated with TMS-acetylene under palladium chemistry to provide their corresponding ethynylaryl derivatives. A library of 15 dimeric members was then obtained using Lewis acid catalyzed glycosidation, aryl-aryl homocoupling, transition metal catalyzed Sonogashira cross-coupling reactions, and oxidative Glaser homocoupling.

Full text of DOI:10.1016/j.carres.2011.03.041

Carbohydrate Research 346 (2011) 1479–1489
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of a small library of bivalent
cross-linking
a-D-mannopyranosides for lectin
⇑
Milan Bergeron-Brlek, Tze Chieh Shiao, M. Corazon Trono, René Roy
PharmaQAM, Department of Chemistry, Université du Québec à Montréal, PO Box 8888, Succ. Centre-Ville, Montréal (Québec), Canada H3C 3P8
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 6 April 2011
A small library of bivalent
evaluate the effects of inter-saccharide distances upon multivalent binding interactions with plant and
a-D-mannopyranosides having rigid linkers was constructed in order to
bacterial lectins. To this end, iodoaryl and propargyl -mannopyranosides were synthesized and the
a
-D
Dedicated to Professor András Lipták
former treated with TMS-acetylene under palladium chemistry to provide their corresponding
ethynylaryl derivatives. A library of 15 dimeric members was then obtained using Lewis acid catalyzed
glycosidation, aryl–aryl homocoupling, transition metal catalyzed Sonogashira cross-coupling reactions,
and oxidative Glaser homocoupling.
Keywords:
Library
Mannopyranosides
Lectin
Ó 2011 Elsevier Ltd. All rights reserved.
Cross-linking
Palladium catalysis
1. Introduction
mannosides, it was also found that a trimeric structure had the
highest affinity for galectin-3 while a tetramer was more selective
Carbohydrate–protein interactions are ubiquitous in biological
systems,1 and nature uses multivalent binding strategies to com-
pensate for the commonly low affinity and poor selectivity of car-
bohydrate ligands.2–10 This phenomenon has been particularly well
documented for soluble proteins (lectins) possessing multiple and
often homologous carbohydrate recognition domains (CRDs). For
instance, this is mainly the case for the family of galectins, man-
nose binding proteins, and sialoadhesins that bind to their respec-
tive carbohydrate ligands with more or less similar affinity. Toward
decoding promiscuous receptor’s CRDs against the given families
of carbohydrate ligands, it has been observed that combining mul-
tivalency together with glycomimetic design could further en-
hance discrimination and selectivity.11–15
for galectins-1 and -5.19 These results point toward combining the
above strategies for the syntheses of more potent and selective car-
bohydrate ligands.
Consequently, if one next merges the intrinsic capacities of
small mannoside clusters to form discrete macroscopic architec-
tures with paucivalent lectins following variable cross-linking
processes, it appears further possible to modulate both thermo-
dynamic and kinetic parameters.20–29 This report describes various
strategies aiming at the synthesis of a small library of mannopy-
ranoside dimers toward their relative lectin cross-linking abilities.
The systematic design of a family of divalent mannosylated archi-
tectures built around more rigid scaffolds is thus proposed. This
small chemical glycolibrary will be useful in pursuing our system-
atic investigations regarding the functions played by the subtle but
critical modulations of structural parameters responsible for high
avidity, with specific and tailored presentation of peripheral recog-
nition moieties. By virtue of their flexible scaffolds and linkers, pre-
vious glycodendrimers showed negative cooperativity upon
binding to lectins as shown by their increasingly contributing
entropic loss.21 Hence, by designing rigidified scaffolds with less
flexible conformational and translational mobilities, we aimed at
counterbalancing the negative effects observed with flexible scaf-
folds such as PAMAM, PPI, and polyesters.
Moreover, Sharon has previously demonstrated that bacterial
lectins at the tip of fimbriatedEscherichia coli (FimH) possess subtle
but superior affinities for aromatic a-D-mannopyranoside residues,
thus illustrating the effect of what was coined ‘subsite-assisted
aglycone binding’.16,17 For example, para-nitrophenyl and umbel-
liferyl
inhibitory properties in comparison to methyl
side (Me
Man).16–18 Additionally, discrete differences can be ob-
a-
D-mannopyranosides showed 69- to 1015-fold increased
a
-D
-mannopyrano-
a
served between the inhibitory properties of a given mannoside
derivative against different strains of bacteria, thus illustrating
again that selectivity is achievable. Using galactoside clusters hav-
ing similar aromatic aglycones to those described herein for the
2. Results and discussion
⇑
In our continued efforts to prepare potent ligands of improved
binding selectivity against mannose binding proteins,30–33 we
Corresponding author. Tel./fax: +1 514 9873000x2546.
E-mail address: roy.rene@uqam.ca (R. Roy).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.03.041

1480
M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
describe herein the syntheses of mannoside dimers having inter-
saccharidic rigid linkers that were built using palladium(0)-
catalyzed cross-coupling Sonogashira reactions34 and oxidative
copper-catalyzed alkyne homocoupling (Glaser reaction).35
The initial methodology followed for the synthesis of the dimer
library was based on the Lewis-acid promoted O-glycosidation of 1
using various diols (Scheme 1). Giovenzena et al.36 reported the
synthesis of 2-butyne-1,4-di-yl glucoside from 2-butyne-1,4-diol
promoted by trimethylsilyltriflate. A yield of 34% was reported
for the b-anomer. Reacting peracetylated mannose and bisphenol
dimers. Thus, double Pd(0)-catalyzed treatment of 11 onto 1,4-
diiodobenzene 17 afforded dimer 18 in 88% yield (Scheme 3).31
Analogously, ortho and meta-substituted dimers 21 and 24, teth-
ered on a single benzene core provided by diiodobenzenes 20
and 23, were obtained using optimized conditions with palladium
tetrakistriphenylphosphine as catalyst (Et3N, DMF, 60 °C, 4 h) in
82% and 88% yield, respectively.
Tothisend, aryliodides8–10weretreatedwiththeirethynylben-
zene partners 12–14, to provide symmetrical dimannosides 26,31 28,
and 30, tethered with an acetylene bridge, in essentially quantitative
yields using the same above-mentioned conditions (Pd(PPh3)4, Et3N,
DMF, 60 °C, 4 h) (Scheme 4). Zemplén deprotections of 26, 28, and 30
wereuneventfuland providedunprotectedcompounds27,31 29, and
31 in quantitative yields. In order to further develop the possibility
offered by these intermediates, cross-coupling of 4-iodophenyl
mannoside 8 with propargyl mannoside 11 was achieved using the
same conditions to provide unsymmetrical dimer 32 in 98% yield.31
Quantitative de-O-acetylation under Zemplén conditions afforded
dimer 33. Since it was anticipated that the cross-coupling of 11 with
compounds 9 and 10 would provide spatially too closed mannopy-
ranosides, the experiments were not attempted.29
A gave the
a-anomer 3 in 49% yield. Mannoside 6 was obtained
in 59% yield using 2-butyne-1,4-diol, accompanied by 35% of the
O-peracetylated starting material.25,32,33 Given the moderate yields
obtained with the Lewis acid-catalyzed reactions, we next turned
our attention to alternative procedures.
In order to produce suitable building blocks, mannose pentaace-
tate (1) was first treated with the corresponding iodophenols and
boron trifluoride etherate in methylene chloride to provide key
monomeric building blocks para- (8),30 ortho- (9), and meta- (10)
iodophenyl
yield, respectively (Scheme 2). Propargyl
a-D
-mannopyranosides in 76–96%,37 36%, and 63%
a-D-mannopyranoside
11 was also prepared in 76–95% yield by a Lewis acid-catalyzed
reaction between mannose pentaacetate (1) and propargyl
alcohol.30–33,38
To further expand the family of building blocks required for a
versatile library construction, the synthesis of symmetrical dimers
was initiated. Thus, cross-coupling of 8 with (trimethylsilyl)acety-
lene using palladium(0) catalysis, followed by the removal of the
silyl-protecting group with TBAF under buffered conditions (HOAc)
To expand the potential of this family of versatile building
blocks, we further planned increasing the intersaccharidic dis-
tances by intercalating two diacetylene bridges between the aro-
matic residues. This was readily achieved using Glaser oxidative
homocoupling under Hay’s conditions.35,41 Dimers 34, 36, and 38
were thus conveniently prepared in 47–68% yields using copper(II)
acetate in refluxing pyridine for 48 h (Scheme 5). After standard
de-O-acetylation under Zemplén conditions, the corresponding
unprotected dimers 35, 37, and 39 were obtained. For comparison
purpose, diacetylenic dimer 40 was similarly prepared and hydro-
genated under Pd–C to provide 41.29
In conclusion, a panel of symmetrical and unsymmetrical man-
nopyranoside dimers were efficiently synthesized using versatile
building blocks bearing alkynyl as well as iodoaryl functionalities
in the aglycone moieties. Varied palladium-catalyzed homo- and
cross-coupling reactions were shown to be generally superior
toward their syntheses in comparison to more classical Lewis-acid
catalyzed glycosidations of diols. The best yields were obtained
during either homo- or cross-coupling Sonogashira reaction in
the presence of palladium tetrakistriphenylphosphine as catalyst
(Pd(PPh3)4, Et3N, DMF, 60 °C, 4–24 h) (Schemes 3 and 4).
in THF afforded para-ethynylphenyl
a-D-mannopyranoside 12 in
58% overall yield (Scheme 2). Analogous handling on ortho-iodide
9 and meta-iodide 10 gave 13 in only 10% yield and 14 in 55% yield.
An improved preparation of the more hindered ortho isomer 13
was achieved using dichlorobis (triphenylphosphine) palladium(II)
(PdCl2(PPh3)2) in the presence of triphenylphosphine, copper(I)
iodide, and acetylene gas bubbled into the reaction mixture
(DMF, Et3N, 60 °C) and the isomer 13 was obtained in an improved
yield of 44%.
First an Ullmann type palladium-catalyzed aryl–aryl homocou-
pling was attempted.39,40 The homocoupling of 8 was performed
using Pd(OAc)2, potassium acetate (KOAc), and tetrabutyl ammo-
nium bromide in DMF at 130 °C for 4 h to give dimer 15 in 64%
yield (Scheme 3). De-O-acetylation under Zemplén conditions
(NaOMe, MeOH) afforded dimer 16 in quantitative yield. Sono-
gashira coupling conditions were used for the following set of
It is now well admitted that dimeric clusters can provide insol-
uble complexes with tetrameric lectins, but the kinetics of forma-
tion, as well as the nature and stability of the cross-linked
OR
RO
RO
RO
O
2
HO
OH
O
O
OR
OR
O
NaOMe
MeOH
rt, 14 h
3
4
R = Ac
BF3-O2Et, CH2Cl2
rt, 24h, 49%
R = H, quant.
OR
OAc
O
AcO
AcO
AcO
OR
OR
RO
RO
RO
OAc
O
BF3-O2Et, CH2Cl2
rt, 14h, 59%
1
O
O
HO
OH
5
OR
OR
NaOMe
MeOH
rt, 14 h
6
7
R = Ac
O
R = H, quant.
OR
OR
Scheme 1. Synthesis of a-D-mannopyranoside dimers using Lewis acid catalyzed glycosidations of preformed diols.

M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
1481
OAc
O
OAc
O
AcO
AcO
AcO
AcO
OAc
O
I
AcO
AcO
OAc
O
AcO
AcO
AcO
AcO
AcO
HO
AcO
O
I
O
I
O
BF3-O2Et, CH2Cl2
0°C to rt, 12h
OAc
I
1
8 (
95%)
9 (
36%)
10 (
63%)
2. TBAF
1. Pd(PPh3)4
DMF, Et3N
BF3-O2Et, CH2Cl2
0°C to rt, 12-48h
76-95%
HOAc, THF
HO
rt, 2h
60°C, 2-24h
10-58%
TMS
OAc
O
AcO
AcO
OAc
OAc
AcO
AcO
AcO
AcO
AcO
OAc
AcO
AcO
O
O
O
AcO
AcO
AcO
O
O
O
O
11
12
13
14
OAc
O
AcO
AcO
OAc
AcO
AcO
H
H
O
AcO
AcO
PdCl2(PPh3)2
DMF, Et3N
60°C, 7h
44%
O
O
I
9
13
Scheme 2. Syntheses of the key monomeric building blocks.
architectures vary greatly with the type of linkers.25,29 Similarly,
when the carbohydrate ligands bind too strongly (low Kds), the
speed at which the complexes are formed precludes the formations
of favorable equilibrium that would provide well organized and
more stable lattices.29
(d) are reported in ppm downfield from internal reference of resid-
ual solvents. Coupling constants (J) are reported in hertz (Hz), and
the following abbreviations are used: singlet (s), doublet (d), dou-
blet of doublets (dd), triplet (t), multiplet (m), and broad (b). Anal-
ysis and assignments were made using COSY, DEPT, and HETCOR
Preliminary data indicated that more rigid dimer 40 had a Kd 10
experiments. The a-stereochemistry of the O-glycosidic linkages
was ascertained by comparison of experimental JC-1,H-1 coupling
1
times superior than that of MeaMan and the flexible dimer 41 in
binding to bacterial Burkholderia cenocepacia dimeric BC2L-A lec-
tin.29 These results are in contrast to those obtained from tetra-
meric plant lectins isolated from Canavalia ensiformis (ConA) and
Dioclea grandiflora (DGL) wherein the flexible dimer 41 appeared
to be superior.25 These initial results further demonstrate the need
for systematic comparisons between a wide range of oligomeric
carbohydrate binding proteins and glycoclusters/glycodendrimers
of varied valencies. Overall, these data point again toward the fact
that increased binding and selectivity is achievable with an analo-
gous family of similar receptors.42 A detailed comparison of the
above library with various mannopyranoside binding proteins is
under investigation and will be reported in due course.
constants, determined by a coupled HSQC experiment, with known
data for
a-glycosides (ca. 170 Hz). High-resolution mass spectra
(HRMS) were carried out by the University’s analytical laboratory
on a HPLC Agilent Technologies 1200 Series + Agilent Technologies
6210 MS TOF (Université du Québec à Montréal, Canada).
3.2. Procedures
3.2.1. 4,40-Bis-(2,3,4,6-tetra-O-acetyl-
a-D-mannopyranosyloxy)-
diphenylisopropane (3)
Boron trifluoride diethyl etherate (0.95 mL, 7.5 mmol,
1.70 equiv) was added via a syringe to a solution of mannose
pentaacetate 1 (1.72 g, 4.4 mmol, 1.00 equiv) and bisphenol A (2)
(0.49 g, 2.2 mmol, 0.50 equiv) in dry CH2Cl2 (70 mL) cooled to
0 °C and under N2. The solution was allowed to warm up to room
temperature and was further stirred under a stream of N2 for 24 h,
during which time reaction was judged complete by TLC (hexane/
EtOAc 1:1). The reaction mixture was washed with satd NaHCO3
(2 ꢀ 80 mL), 2 M HCl (2 ꢀ 80 mL), and H2O (2 ꢀ 80 mL). The organ-
ic layer was dried over anhydrous Na2SO4, filtered, and the solvent
was removed under reduced pressure. The concentrate was puri-
fied by silica gel chromatography with hexane/EtOAc 1:1 as eluent.
The titled compound 3 was obtained as a white crystalline solid
3. Experimental
3.1. General methods
The reactions were carried out in organic media under nitrogen
atmosphere using freshly distilled solvents (dichloromethane was
freshly distilled under P2O5). Evolution of reactions was monitored
by analytical thin-layer chromatography using Silica Gel 60 F254
precoated plates (E. Merck). Optical rotations were measured with
a JASCO P-1010 polarimeter. Melting points were measured on a
Fisher Jones apparatus and are uncorrected. Arabic numerals in
ascending order are given to the residues from the reducing end.
NMR spectra were recorded on Varian Gemini 300 and Varian In-
nova 600 MHz spectrometers. Proton and carbon chemical shifts
(0.8 g, 49% yield); mp 79–81 °C; ½a D23
ꢁ
+62.7 (c 1.0, CHCl3); 1H
3
NMR (CDCl3, 600 MHz): d 7.10 (d, JH,H 8.8 Hz, 4H, Har), 6.90 (d,
3
3
3JH,H 8.8 Hz, 4H, Har), 5.52 (dd, J3,2 3.4 Hz, J3,4 10.0 Hz, 2H,
3
3
2 ꢀ H-3), 5.46 (s, 2H, 2 ꢀ H-1), 5.39 (dd, J1,2 1.8 Hz, J2,3 3.3 Hz,

1482
M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
OR
RO
RO
RO
OAc
O
O
AcO
AcO
TBABr, KOAc
Pd(OAc)2
AcO
O
O
DMF, 130°C, 4h
64%
O
OR
OR
I
O
NaOMe
15 R = Ac
R = H, quant.
8
MeOH
rt, 14 h
16
OR
OR
OR
RO
RO
RO
I
I
O
OAc
AcO
AcO
O
17
AcO
O
Pd(PPh3)4
DMF, Et 3N
60°C, 4h
O
O
OR
OR
quant. Ref. 32
O
18
19
NaOMe
MeOH
rt, 14 h
R = Ac
R = H, quant.
11
OR
OR
Pd(PPh3)4
DMF, Et3N
60°C, 4h
82%
Pd(PPh3)4
I
I
DMF, Et3N
60°C, 4h
88%
20
I
OR
RO
RO
RO
OR
RO
I
O
O
RO
23
RO
O
O
O
24
25
NaOMe
R = Ac
R = H, quant.
O
OR
OR
MeOH
rt, 14 h
O
NaOMe
MeOH
rt, 14 h
OR
OR
21 R = Ac
R = H, quant.
O
OR
OR
22
OR
OR
Scheme 3. Palladium(0)-catalyzed syntheses of dimeric mannopyranosides using aryl–aryl homocoupling and a double Sonogashira cross-coupling reaction.
3
2H, 2 ꢀ H-2), 5.33 (t, J3,4 = 3J4,5 10.0 Hz, 2H, 2 ꢀ H-4), 4.25 (dd,
3.2.3. 1,4-Bis-(2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyloxy)-
but-2-yne (6)
To a solution of 1 (880 mg, 2.25 mmol, 2.40 equiv) in dry dichlo-
romethane (6 mL) was added dropwise boron trifluoride diethyl
3J5,6a 4.9 Hz, J6a,6b 12.1 Hz, 2H, 2 ꢀ H-6a), 4.11–4.03 (m, 4H,
2
2 ꢀ H-5 and H-6b), 2.12, 2.02, 2.00, 1.99 (4 ꢀ s, 4 ꢀ 6H, COCH3),
1.60 (s, 6H, Ph-C(CH3)2); 13C NMR (CDCl3, 150 MHz) d 171.1,
170.45, 169.9, 169.9, 169.7 (C@O), 153.6, 145.2, 127.8, 127.7
(C6H4), 95.9 (C-1), 69.4 (C-5), 69.0 (C-2), 68.9 (C-3), 62.5 (C-4),
62.1 (C-6), 41.9 (Ph-C(CH3)2), 30.9 (Ph-C(CH3)2), 21.0, 20.8, 20.6
(COCH3); FAB-HRMS m/z calcd for C43H52O20 [M+K]+ 927.2689,
found, 927.2997; Anal. Calcd for C43H52O20: C, 58.10; H, 5.90.
Found, C, 57.75; H, 5.92.
etherate (537 lL, 4.27 mmol, 4.56 equiv) at 0 °C under nitrogen
atmosphere. The mixture was stirred at room temperature for
3 h. Then, 2-butyne-1,4-diol (5) (81.5 mg, 0.937 mmol, 1.00 equiv)
in acetonitrile (4 mL) was added to the solution and stirred at room
temperature over night. Et3N (606 lL, 4.27 mmol, 4.56 equiv) was
added to solution at 0 °C and after evaporation of the solvent, the
resulting crude product was purified by column chromatography
on silica gel using gradient elution (hexane 100% to hexane/EtOAc
4:6). Compound 6 was obtained as a white crystalline solid
3.2.2. 4,40-Bis-(
a-D-mannopyranosyloxy)diphenylisopropane (4)
The titled compound was obtained by deacetylation of 3
(0.110 g, 0.12 mmol) using MeOH (0.9 mL) to which was added a
solution of 1 M NaOMe in MeOH to set the pH at 8–9. The reaction
was stirred at room temperature for 14 h and was then neutralized
by the addition of acidic Amberlyst resin (IR-120). The solution was
filtered, concentrated under reduced pressure and lyophilizated to
afford 4 as a yellowish solid (0.065 g, 95% yield); mp 114–116 °C;
(414 mg, 59% yield); Rf (hexane/EtOAc 4:6) 0.33; mp 52–53 °C;
3
½
a 2D0
ꢁ
+67.0 (c 1, CHCl3); 1H NMR (CDCl3, 600 MHz) d 5.31 (dd, J2,3
3.4 Hz, J3,4 10.0 Hz, 2H, 2 ꢀ H-3), 5.27 (t, J3,4 = 3J4,5 10.0 Hz, 2H,
3
3
3
3
3
2 ꢀ H-4), 5.24 (dd, J1,2 1.7 Hz, J2,3 3.4, 2H, 2 ꢀ H-2), 4.97 (d, J1,2
1.7 Hz, 2H, 2 ꢀ H-1), 4.33–4.24 (m, 6H, 2 ꢀ OCH2, and H-6a), 4.08
3
3
(dd, J6a,6b 2.5 Hz, J5,6 12.2 Hz, 2H, 2 ꢀ H-6b), 3.98 (m, 2H, H-5),
2.14, 2.08, 2.02, 1.96 (4 ꢀ s, 4 ꢀ 6H, COCH3); 13C NMR (CDCl3,
150 MHz) d 170.5, 169.8, 169.7, 169.6 (C@OCH3), 96.0 (C-1), 81.5
(C„C), 69.2 (C-2), 68.9 (C-5), 68.8 (C-3), 65.9 (C-4), 62.2 (C-6),
54.8 (OCH2), 20.8, 20.6, 20.6, 20.5 (4 ꢀ COCH3). FAB-HRMS m/z
calcd for C32H42O20 [M+H]+ 747.2347, found, 747.2221.
½
a 2D2 +107.5 (c 1.6, DMF); 1H NMR (DMSO-d6, 300 MHz) d 7.11 (d,
ꢁ
3JH,H 8.8 Hz, 4H, Har), 7.00 (d, JH,H 8.8 Hz, 4H, Har), 5.30 (d, J1,2
1.6 Hz, 2H, 2 ꢀ H-1), 3.92 (br s, 6H, 2 ꢀ C2-OH, C3-OH, and C4-
OH), 3.78 (t, J 2.9 Hz, 2H, 2 ꢀ C6-OH), 3.62–3.55 (m, 6H, 2 ꢀ H-2,
H-3, and H-4), 3.47–3.16 (m, 6H, 2 ꢀ H-5, H-6a, and H-6b), 2.07
(s, 12H, 2 ꢀ Ph-C(CH3)2); 13C NMR (DMSO-d6, 75 MHz) d 154.4,
143.9, 127.6, 116.2 (C6H4), 99.1 (C-1), 74.9, 70.7, 70.2, 67.0, 66.8
(C-2, C-3, C-4, C-5) 61.1 (C-6), 30.7 [Ph2C(CH3)2], 25.2 (Ph2C(CH3)2);
ESI+-MS m/z calcd for C27H36O12 [M+NH4]+ 570.3, found, 570.3.
3
3
3.2.4. 1,4-Bis-(a-D-mannopyranosyloxy)but-2-yne (7)
The titled compound was obtained as a white solid by deacety-
lation of 6 (0.170 g, 0.23 mmol) using the method described above

M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
1483
OR
RO
RO
RO
O
O
Pd(PPh3)4, DMF
Et3N, 60°C, 24h
8
+
12
quant., Ref. 33
O
OR
OR
NaOMe
26
27
R = Ac
O
MeOH
rt, 14 h
R = H, quant.
OR
OR
OR
O
RO
RO
RO
Pd(PPh3)4, DMF
Et3N, 60°C, 24h
O
9
+
13
80%
O
NaOMe
MeOH
rt, 14 h
28
29
R = Ac
R = H, quant.
OR
OR
O
OR
OR
OR
RO
RO
RO
O
O
Pd(PPh3)4, DMF
Et3N, 60°C, 24h
10
+
14
80%
O
NaOMe
30 R = Ac
31
OR
OR
MeOH
rt, 14 h
R = H, quant.
O
OR
OR
OR
O
RO
RO
RO
OR
Pd(PPh3)4, DMF
Et3N, 60°C, 24h
OR
O
OR
OR
O
8
+
11
98%, Ref. 33
O
NaOMe
MeOH
rt, 14 h
32 R = Ac
R = H, quant.
33
Scheme 4. Palladium(0)-catalyzed syntheses of dimeric mannopyranosides using Sonogashira cross-coupling reaction.
for 4 (0.093 g, quant. yield); Rf (EtOAC/MeOH/H2O 6:3:1); mp 127–
boron trifluoride diethyl etherate (188 lL, 1.50 mmol, 1.50 equiv)
128 °C 0.46; ½a 2D2
ꢁ
+122.1 (c 1, MeOH); 1H NMR (CDCl3, 600 MHz) d
at 0 °C under nitrogen atmosphere. The mixture was stirred at
room temperature overnight and the course of the reaction was
monitored by TLC (hexane/EtOAc 1:1) until complete disappear-
ance of the starting material (12–48 h). CH2Cl2 (50 mL) was added
and the solution was washed with a 20% aqueous Na2CO3 solution
(2 ꢀ 100 mL) and water (2 ꢀ 100 mL). The organic phase was then
dried with anhydrous Na2SO4 and, after evaporation of the solvent,
the resulting crude product was purified by flash chromatography
(hexane/EtOAc 4:1) to give the titled compound 8 as a white solid
(520 mg, 95% yield).37 The titled compound was crystallized in
petroleum ether with a little amount of dichloromethane; Rf (hex-
ane/EtOAc 1:1) 0.61; mp 127–129 °C (from CH2Cl2/PE) (Lit. mp
5.04 (d, 3J1,2 1.3 Hz, 2H, 2 ꢀ H-1), 4.42–4.31 (m, 4H, 2 ꢀ OCH2C„C),
3.97 (dd, 3J2,3 3.1 Hz, 2H, 2 ꢀ H-2), 3.90–3.67 (m, 10H, 2 ꢀ H-4, H-3,
H-6a, H-6b, and H-5); 13C NMR (150 MHz, CDCl3) d 98.9 (C-1), 82.2
(C„C), 73.2 (C-2), 70.6 (C-5), 70.0 (C-3), 66.7 (C-4), 60.9 (C-6),
54.8 ppm (OCH2). ESI+-HRMS m/z calcd for C16H26O12 [M+Na]+
433.1316, found, 433.1312.
3.2.5. 4-Iodophenyl 2,3,4,6-tetra-O-acetyl-a-D-
mannopyranoside (8)
To a solution of penta-O-acetyl-a,b-D-mannopyranose 1 (390
mg, 1.00 mmol, 1.00 equiv) and 4-iodophenol (889 mg, 4.00 mmol,
4.00 equiv) in dry dichloromethane (10 mL) was added dropwise
127–129 °C);31
½
a 2D2 +65 (c 1.0, CHCl3) (Lit. 65 c 1.0, CHCl3);18,30,31
ꢁ

1484
M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
OR
RO
RO
O
RO
OAc
O
AcO
AcO
O
AcO
Cu(OAc)2
O
C5H5N, Δ, 48h
47%
O
12
NaOMe
MeOH
rt, 14 h
OR
OR
34 R = Ac
35
O
R = H, quant.
OR
OR
OR
RO
RO
O
RO
OAc
O
AcO
AcO
O
AcO
Cu(OAc)2
O
C5H5N, Δ, 48h
63%
O
13
OR
OR
NaOMe
MeOH
rt, 14 h
O
36 R = Ac
37
R = H, quant.
OR
OR
OR
O
RO
RO
OAc
O
AcO
AcO
RO
O
Cu(OAc)2
AcO
OR
OR
O
O
OR
C5H5N, Δ, 48h
O
58%
OR
NaOMe
MeOH
rt, 14 h
38
39
R = Ac
14
R = H, quant.
OH
OH
1. CuCl, O2, TMEDA
DMF, 40°C, 4h, 99%
HO
HO
OH
OH
O
HO
O
11
OH
2. MeONa/MeOH
Rt, 1h30, 99%
Ref. 29
O
O
H2, Pd/C, EtOH
rt, 14h, 99%
Ref. 30
40
OH
HO
HO
OH
O
O
OH
HO
OH
OH
O
O
41
Scheme 5. Palladium(0)-catalyzed syntheses of dimeric mannopyranosides using Glaser homocoupling reactions.
3
1H NMR (CDCl3, 300 MHz) d 7.56 (d, JH,H 8.2 Hz, 2H, Har-meta),
3.2.6. 2-Iodophenyl 2,3,4,6-tetra-O-acetyl-a-D-
mannopyranoside (9)
3
3
3
6.84 (d, JH,H 8.3 Hz, 2H, Har-ortho), 5.50 (dd, J2,3 3.4 Hz, J3,4
3
3
10.0 Hz, 1H, H-3), 5.46 (d, J1,2 1.9 Hz, 1H, H-1), 5.40 (dd, J1,2
Treatment of 1 (1.0 g, 2.60 mmol, 1.00 equiv) with 2-iodophenol
(1.0 g, 4.40 mmol, 1.69 equiv) and boron trifluoride diethyl ether-
ate (0.60 mL, 4.70 mmol, 1.81 equiv) as above yielded 9 in 36%
yield (0.5 g). The course of the reaction was followed by TLC (hex-
ane/EtOAc 1:1) until complete disappearance of the starting mate-
rial (17 h). CH2Cl2 (60 mL) was added and the solution was washed
with a 20% aqueous Na2CO3 solution (2 ꢀ 100 mL) and water
(2 ꢀ 100 mL). The organic phase was then dried with anhydrous
Na2SO4 and, after evaporation of the solvent, the resulting crude
1.9 Hz, J2,3 3.4 Hz, 1H, H-2), 5.33 (t, J3,4 = 3J4,5 10.0 Hz, 1H, H-4),
3
3
3
2
4.24 (dd, J5,6a 5.5 Hz, J6a,6b 12.4 Hz, 1H, H-6a), 4.04–4.00 (m, 2H,
H-5, and H-6b), 2.16, 2.02, 2.00, 1.99 (4 ꢀ s, 4 ꢀ 3H, COCH3); 13C
NMR (CDCl3, 75 MHz) d 170.4, 169.9, 169.8, 169.6 (C@O), 155.3,
1
138.4, 118.7 (C6H4), 95.7 (C-1, JC-1,H-1 174.4 Hz), 85.8 (C6H4), 69.2
(C-5), 69.2 (C-2), 68.7 (C-3), 65.8 (C-4), 62.0 (C-6), 20.8–20.6
(COCH3); ESI+-MS m/z calcd for C20H23IO10 [M+Na]+ 573.02; found,
573.06.

M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
1485
product was purified by flash chromatography (hexane/EtOAc 3:2)
to give the titled compound 9 as a white solid (0.5 g, 36% yield); mp
OCH2C„CH), 2.12, 2.07, 2.01, 1.96 (4 ꢀ s, 4 ꢀ 3H, CH3); 13C NMR
(CDCl3, 75 MHz) d 170.5, 169.9, 169.7, 169.6 (C@O), 96.1 (C-1, JC-
143–144 °C; ½a 2D3
ꢁ
+32.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 600 MHz) d
173.4 Hz), 77.8 (OCH2C„CH), 75.5 (OCH2C„CH), 69.2 (C-5),
1,H-1
7.76 (dd, JH,H 1.6 Hz, JH,H 7.8 Hz, 1H, Har), 7.26 (m, 1H, Har), 7.05 (dd,
JH,H 1.3 Hz, JH,H 8.3 Hz, 1H, Har), 6.79 (ddd, JH,H 1.3 Hz, JH,H 7.6 Hz,
68.9 (C-3), 68.8 (C-2), 65.9 (C-4), 62.2 (OCH2C„CH), 54.9 (C-6),
20.8, 20.7, 20.6, 20.6 (COCH3); ESI+-HRMS m/z calcd for C17H22O10
[M+Na]+ 409.1105, found, 409.1100.
3
3
JH,H 8.9 Hz, 1H, Har), 5.68 (dd, J2,3 3.4 Hz, J3,4 10.1 Hz, 1H, H-3),
3
3
3
5.55 (d, J1,2 1.8 Hz, 1H, H-1), 5.51 (dd, J1,2 1.9 Hz, J2,3 3.4 Hz,
1H, H-2), 5.38 (t, J3,4 = 3J4,5 10.1 Hz, 1H, H-4), 4.25 (dd, J5,6a
3.2.9. 4-Ethynylphenyl 2,3,4,6-tetra-O-acetyl-a-D-
mannopyranoside (12)
Tetramethylsilylacetylene (0.500 mL, 3.50 mmol, 1.84 equiv)
was added via a syringe, to a solution of 4-iodophenyl 2,3,4,6-
tetra-O-acetyl-a-D-mannopyranoside (8) (1.00 g, 1.90 mmol,
3
3
2
3
5.2 Hz, J6a,6b 12.2 Hz, 1H, H-6a), 4.09 (m, 1H, H-5), 4.04 (dd, J5,6b
2
2.2 Hz, J6a,6b 12.2 Hz, 1H, H-6b), 2.17, 2.04, 2.01, 2.00 (4 ꢀ s,
4 ꢀ 3H, COCH3); 13C NMR (CDCl3, 150 MHz) d 170.4, 169.9, 169.7,
169.7 (C@O), 154.4, 139.7, 129.4, 124.7, 115.0 (C6H4), 95.2 (C-1,
1JC-1,H-1 174.2 Hz), 87.3 (C6H4), 69.8 (C-5), 69.3 (C-2), 68.9 (C-3),
65.8 (C-4), 62.0 (C-6), 20.8, 20.7, 20.6, 20.6 (COCH3); ESI+-MS m/z
calcd for C20H23IO10 [M+H]+ 551.04, found, 551.13.
1.00 equiv) and palladium tetrakistriphenyl phosphine (Pd(PPh3)4)
(0.110 g, 0.09 mmol, 0.05 equiv) in a mixture of Et3N–DMF (60–
1 mL), kept under nitrogen. The reaction mixture was heated to
60 °C for 24 h at which time reaction was judged complete by
TLC (hexane/EtOAc 1:1). The reaction mixture was diluted with
EtOAc (60 mL) washed with 2 M HCl (3 ꢀ 100 mL), saturated NaH-
CO3 (2 ꢀ 100 mL) and H2O (2 ꢀ 100 mL), and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
concentrate was passed through a short silica gel column with hex-
ane/EtOAc 1:1 as eluent. The solvent was removed under reduced
pressure. The concentrate was dissolved in 20 mL THF. A solution
of 10 drops of tetrabutylammonium fluoride (1 M in THF) and 1
drop of acetic acid in 2 mL of THF was added dropwise. After 2 h,
the solvent was removed in vacuo. The product was purified by sil-
ica gel column chromatography using hexane/EtOAc 2:1 as eluent
to yield the pure compound 12 as a yellow solid (0.5 g, 58% yield);
3.2.7. 3-Iodophenyl 2,3,4,6-tetra-O-acetyl-a-D-
mannopyranoside (10)
Treatment of 1 (2.0 g, 5.20 mmol, 1.00 equiv) with 3-iodophenol
(2.1 g, 9.40 mmol, 1.81 equiv) and boron trifluoride diethyl ether-
ate as above (1.1 mL, 8.7 mmol, 1.67 equiv) yielded 10 in 63% yield
(1.2 g) The course of the reaction was followed by TLC (hexane/
EtOAc 1:1) until complete disappearance of the starting material
(22 h). CH2Cl2 (80 mL) was added and the solution was washed
with a 20% aqueous Na2CO3 solution (2 ꢀ 100 mL) and water
(2 ꢀ 100 mL). The organic phase was then dried with anhydrous
Na2SO4 and, after evaporation of the solvent, the resulting crude
product was purified by flash chromatography (hexane/EtOAc
2:1) to give 3-iodophenyl 2,3,4,6-tetra-O-acetyl-
a
-
D
-mannopyran-
mp 93–95 °C; ½a 2D3
ꢁ
+33.8 (c 1.3, CHCl3); IR (neat): 3277, 2960, 2108,
oside 10 as a white solid (1.2 g, 63% yield); mp 108–109 °C; ½a D23
ꢁ
1751, 1228, 1036, 837, 758 cmꢂ1; 1H NMR (CDCl3, 600 MHz) d 7.41
(d, 3JH,H 8.9 Hz, 2H, Har), 7.01 (d, 3JH,H 8.8 Hz, 2H, Har), 5.48 (dd, 3J2,3
+41.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 600 MHz) d 7.47 (dd, JH,H
1.7 Hz, JH,H 2.0 Hz, 1H, Har), 7.37 (ddd, JH,H 1.3 Hz, JH,H 2.9 Hz, JH,H
3
3
3.5 Hz, J3,4 10.1 Hz, 1H, H-3), 5.50 (d, J1,2 1.4 Hz, 1H, H-1), 5.40
3
3
3
3
3
7.5 Hz, 1H, Har), 7.01 (m, 2H, Har), 5.49 (dd, J3,2 3.5 Hz, J3,4
(dd, J1,2 2.0 Hz, J2,3 3.6 Hz, 1H, H-2), 5.32 (t, J3,4 = 3J4,5 10.1 Hz,
3
3
3
2
10.0 Hz, 1H, H-3), 5.46 (d, J1,2 1.8 Hz, 1H, H-1), 5.38 (dd, J1,2
1H, H-4), 4.23 (dd, J5,6a 5.7 Hz, J6a,6b 12.4 Hz, 1H, H-6a), 4.03 (m,
2H, H-5, H-6b), 3.00 (s, 1H, C„CH), 2.16, 2.02, 2.00, 1.99 (4 ꢀ s,
4 ꢀ 3H, COCH3); 13C NMR (CDCl3, 150 MHz) d 170.4, 169.9, 169.8,
169.6 (C@O), 155.7, 133.6, 116.4 (C6H4), 95.6 (C-1), 82.9, 76.6
(C„C), 69.3 (C-5), 69.2 (C-2), 68.7 (C-3), 65.8 (C-4), 62.0 (C-6),
20.8, 20.6, 20.6 (COCH3); FAB-MS m/z calcd for C22H24O10 [M+K]+
487.10; found, 486.70.
3
3
1.9 Hz, J2,3 3.6 Hz, 1H, H-2), 5.31 (t, J3,4 = 3J4,5 10.1 Hz, 1H, H-4),
3
2
4.24 (dd, J5,6a 6.0 Hz, J6a,6b 12.3 Hz, 1H, H-6a), 4.10–4.03 (m, 2H,
H-5, H-6b), 2.16, 2.03, 2.02, 2.00 (4 ꢀ s, 4 ꢀ 3H, COCH3); 13C NMR
(CDCl3, 150 MHz) d 170.4, 169.8, 169.5, 169.6 (C@O), 155.9,
1
132.2, 130.9, 125.6, 116.1 (C6H4), 95.8 (C-1, JC-1,H-1 173.8 Hz),
94.1(C6H4), 69.3 (C-5), 69.2 (C-2), 68.7 (C-3), 65.8 (C-4), 62.1 (C-
6), 20.8, 20.7, 20.6 (COCH3); FAB-MS m/z calcd for C20H23IO10
[M+H]+ 551.04, found, 551.13.
3.2.10. 2-Ethynylphenyl 2,3,4,6-tetra-O-acetyl-a-D-
mannopyranoside (13)
3.2.8. Prop-2-ynyl 2,3,4,6-tetra-O-acetyl-
a
-D
-mannopyranoside
Compound 9 (0.100 g, 0.190 mmol, 1.00 equiv) in Et3N (30 mL)
(11)
was stirred under N2 for 30 min. Dichloro-bis(triphenyl)phoshine
To a solution of 1 (250 mg, 0.64 mmol, 1.00 equiv) in dry dichlo-
romethane (10 mL) was added boron trifluoride etherate (150 L,
1.19 mmol, 1.90 equiv), dropwise at 0 °C under nitrogen. The mix-
palladium(II) (PdCl2(PPh3)2) (1.6 mg, 0.23
added to the mixture. After 5 min of stirring under N2, copper(I) io-
dide (CuI) (3.9 mg, 2.5 mol, 0.01 equiv) and triphenyl phosphine
(PPh3) (3.5 mg, 0.13 mol, 0.0007 equiv) were added to the mix-
lmol, 0.001 equiv) was
l
l
ture was allowed to warm up, and stirred at room temperature for
l
4 h. Propargyl alcohol (150
l
L, 2.56 mmol, 4.00 equiv) was added,
ture and stirred for a further 5 min. Acetylene gas was bubbled
through the reaction mixture, which was then heated to 60 °C.
The reaction was followed by TLC (hexane/EtOAc 2:1) and was
judged to be complete after 7 h. The solvent was removed under
reduced pressure and the concentrate was then passed through a
column of silica gel, with hexane/EtOAc 2:1 as eluent. The purified
product 13 was obtained as a white solid (0.037 g, 44% yield); mp
and the mixture was stirred at room temperature until TLC (hex-
ane/EtOAc 1:1) showed complete disappearance of the starting
material (12–48 h). After the addition of CH2Cl2 (20 mL), the solu-
tion was washed successively with 20% aqueous Na2CO3 solution
(2 ꢀ 40 mL) and water (2 ꢀ 40 mL). The organic phase was dried,
concentrated, and chromatography (hexane/EtOAc 2:1) gave the
titled compound 11, which crystallized after drying under vacuum
(234 mg, 95% yield). Crystallization from CH2Cl2–petroleum ether
and recrystallization from petroleum ether gave material melting
127–130 °C; ½a 2D3
ꢁ
+38.3 (c 1.2, CHCl3); IR (neat): 3271, 2907, 1742,
1240, 1137, 760 cmꢂ1
;
1H NMR (CDCl3, 600 MHz) d 7.45 (dd, JH,H
1.6 Hz, JH,H 7.6 Hz, 1H, Har), 7.27 (ddd, JH,H 1.7 Hz, JH,H 7.7 Hz, JH,H
8.5 Hz, 1H, Har), 7.08 (d, JH,H 8.1 Hz, 1H, Har), 7.01 (ddd, JH,H
at 99–100 °C, Lit. 99–100 °C;31
½
a 2D2
ꢁ
+56 (c 2.0, CHCl3) [Lit. ½a D22
ꢁ
+56 (c 2.0, CHCl3)];31 1H NMR (CDCl3, 300 MHz) d 5.31 (dd, J2,3
0.9 Hz, JH,H 7.6 Hz, JH,H 8.5 Hz, 1H, Har), 5.63 (dd, J2,3 3.5 Hz, J3,4
3
3
3
3
3
3
3
3.4 Hz, J3,4 10.0 Hz, 1H, H-3), 5.26 (t, J3,4 = 3J4,5 10.0 Hz, 1H, H-
10.1 Hz, 1H, H-3), 5.57 (d, J1,2 1.8 Hz, 1H, H-1), 5.3 (dd, J1,2
3
3
3
3
3
4), 5.23 (dd, J1,2 1.7 Hz, J2,3 3.4, 1H, H-2), 4.99 (d, J1,2 1.7 Hz,
1.9 Hz, J2,3 3.5 Hz, 1H, H-2), 5.35 (t, J3,4 = 3J4,5 10.1 Hz, 1H, H-4),
3
2
3
2
1H, H-1), 4.24 (dd, J5,6b 5.2 Hz, J6a,6b 12.2 Hz, 1H, H-6a), 4.24 (d,
4.24 (dd, J5,6a 5.4 Hz, J6a,6b 12.1 Hz, 1H, H-6a), 4.19 (m, 1H, H-5),
4.05 (dd, 3J5,6b 2.1 Hz, 2J6a,6b 12.1 Hz, 1H, H-6b), 3.32 (s, 1H, C„CH),
2.17, 2.03, 2.00, 1.99 (4 ꢀ s, 4 ꢀ 3H, COCH3); 13C NMR (CDCl3,
4JH,H 2.4 Hz, 2H, OCH2C„CH), 4.07 (dd, J5,6b 2.5 Hz, J6a,6b
3
2
4
12.2 Hz, 1H, H-6a), 4.00 (m, 1H, H-5), 2.44 (t, JH,H 2.4 Hz, 1H,

1486
M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
150 MHz) d 170.4, 169.9, 169.7, 169.7 (C@O), 156.6, 133.9, 130.0,
123.1, 115.6, 113.6 (C6H4), 96.4 (C-1), 82.4, 78.8 (C„C), 69.6 (C-
5), 69.5 (C-2), 68.8 (C-3), 65.9 (C-4), 62.1 (C-6), 20.8, 20.7, 20.6,
20.6 (COCH3); FAB-MS m/z calcd for C22H24O10 [M+K]+ 487.10,
found, 487.14.
ESI+-HRMS m/z calcd for C40H46O20 [M+K]+ 885.2214, found,
885.2198.
3.2.13. 4,40-Bis-(
a-D-mannopyranosyloxy)biphenyl (16)
The titled compound was obtained as a yellowish solid by
deacetylation of 15 (0.077 g, 0.09 mmol) using the method de-
scribed above for 4 (0.046 g, quant. yield); decomposed at 220–
3.2.11. 3-Ethynylphenyl 2,3,4,6-tetra-O-acetyl-a-D-
mannopyranoside (14)
225 °C; ½a 2D3
ꢁ
+129.6 (c 1, DMSO); 1H NMR (DMSO-d6 and D2O ex-
3
3
Tetramethylsilylacetylene (0.77 mL, 5.40 mmol, 2.00 equiv) was
added via a syringe, to a solution of 3-iodophenyl 2,3,4,6-tetra-O-
acetyl-mannopyranoside (10) (1.50 g, 2.70 mmol, 1.00 equiv) and
palladium tetrakistriphenyl phosphine (Pd(PPh3)4) (0.17 g,
0.10 mmol, 0.04 equiv) in a mixture of Et3N–DMF (30–3 mL), kept
under nitrogen. The reaction mixture was heated to 60 °C for 2½ h
during which time the reaction was judged complete by TLC (hex-
ane/EtOAc 1:1). The reaction mixture diluted with EtOAc (40 mL)
was washed with 2 M HCl (3 ꢀ 80 mL), saturated NaHCO3
(2 ꢀ 80 mL) and H2O (2 ꢀ 80 mL) and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and
the concentrate was passed through a short silica gel column using
hexane/EtOAc 1:1 as eluent. The solvent was removed in vacuo.
The concentrate was dissolved in 20 mL THF. A solution of 5 drops
tetrabutylammonium fluoride (1 M in THF), 5 drops of acetic acid,
and 5 mL THF was added dropwise. After 2 h, the solvent was re-
moved in vacuo. The product was purified by silica gel column
chromatography using hexane/EtOAc 2:1 as eluent to yield the
change, 300 MHz) d 7.50 (d, JH,H 6.9 Hz, 4H, Har), 7.10 (d, JH,H
6.9 Hz, 4H, Har), 5.38 (s, 2H, 2 ꢀ H-1), 3.86–3.40 (m, 12H, 2 ꢀ H-2,
H-3, H-4, H-5, H-6a, and H-6b); 13C NMR (DMSO-d6, 75 MHz) d
155.7, 133.5, 127.4, 117.2 (C6H4), 99.0 (C-1), 75.1, 70.7, 70.1,
66.7, 61.1 (C-2, C-3, C-4, C-5, and C-6); ESI+-HRMS m/z calcd for
C24H30O12 [M+Na]+ 533.1629, found, 533.1625.
3.2.14. 1,2-Bis-[1,10(2,3,4,6-tetra-O-acetyl-
a-D-
mannopyranosyloxy)prop-2,20-ynyl]benzene (21)
Nitrogen gas was bubbled through a solution of 2-propynyl
2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside (11) (0.400 g, 1.03
mmol, 1.00 equiv) and 1,2-diiodobenzene (20) (0.170 g, 0.51
mmol, 0.50 equiv) in DMF–Et3N (10–10 mL) for 25 min Pd(PPh3)4
(0.054 mg, 0.047 mmol, 0.05 equiv) was added and the mixture
was stirred under N2 for 5 min. The reaction mixture was heated
to 60 °C and stirred under a stream of N2 for 4 h after which time
the reaction was judged complete by TLC (hexane/EtOAc 1:1).
The reaction mixture was cooled and dissolved in diethylether/tol-
uene (100 mL/50 mL), then washed with 2 M HCl (2 ꢀ 150 mL),
with saturated NaHCO3 soln (1 ꢀ 150 mL), and then H2O
(1 ꢀ 150 mL). The crude extract was then purified by column chro-
matography in silica gel with hexane/EtOAc 1:1 as eluent. The
titled compound 21 was obtained as a yellow crystalline solid
pure compound 14 as a yellow gel (0.7 g, 55% yield); ½a D23
ꢁ
+83.4
(c 2.6, CHCl3); IR (neat): 3266, 2960, 1752, 1224, 1135, 757 cmꢂ1
;
1H NMR (CDCl3, 600 MHz) d 7.23 (dd, JH,H 2.5 Hz, 1H, Har), 7.22
(d, JH,H 8.0 Hz, 1H, Har), 7.16 (ddd, JH,H 1.2 Hz, JH,H 2.4 Hz, JH,H
10.0 Hz, 1H, Har), 7.05 (ddd, JH,H 1.1 Hz, JH,H 2.6 Hz, JH,H 8.2 Hz,
1H, Har), 5.51 (dd, J2,3 3.5 Hz, J3,4 10.0 Hz, 1H, H-3), 5.48 (d, J1,2
(0.3532 g, 82% yield); mp 80–84 °C; ½a D23
ꢁ
+51.3 (c 1.5, CHCl3); 1H
NMR (CDCl3, 600 MHz) d 7.38 (d, JH,H 5.8 Hz, 1H, Har), 7.37 (d, JH,H
5.8 Hz, 1H, Har), 7.22 (d, JH,H 5.8 Hz, 1H, Har), 7.21 (d, JH,H 5.8 Hz,
3
3
3
3
3
1.8 Hz, 1H, H-1), 5.40 (dd, J1,2 1.9 Hz, J2,3 3.5 Hz, 1H, H-2), 5.31
(t, J3,4 = 3J4,5 10.0 Hz, 1H, H-4), 4.25 (dd, J5,6a 6.5 Hz, J6a,6b
12.4 Hz, 1H, H-6a), 4.06 (m, 2H, H-5, H-6b), 3.04 (s, 1H, C„CH),
2.16, 2.02, 2.01, 2.01 (4 ꢀ s, 4 ꢀ 3H, COCH3); 13C NMR (CDCl3,
150 MHz) d 170.5, 169.9, 169.8, 169.7 (C@O), 155.3, 129.5, 126.9,
123.4, 119.9, 117.6 (C6H4), 95.8 (C-1), 82.9, 77.6 (C„C), 69.2 (C-
5), 69.2 (C-2), 68.7 (C-3), 65.9 (C-4), 62.1 (C-6), 21.0, 20.8, 20.6,
20.6 (COCH3); FAB-HRMS m/z calcd for C22H24O10 [M+K]+
487.1007, found, 487.1785.
3
3
2
3
3
1H, Har), 5.30 (dd, J3,2 3.3 Hz, J3,4 6.9 Hz, 2H, 2 ꢀ H-3), 5.28 (t,
3J3,4 = 3J4,5 10.5 Hz, 2H, 2 ꢀ H-4), 5.24 (dd, J1,2 1.8 Hz, J2,3 3.3 Hz,
3
3
3
2H, 2 ꢀ H-2), 5.08 (d, J1,2 1.5 Hz, 2H, 2 ꢀ H-1), 4.49 (s, 4H,
3
2
H2CC„C), 4.23 (dd, J5,6a 4.9 Hz, J6a,6b 12.3 Hz, 2H, 2 ꢀ H-6a),
4.05–4.01 (m, 4H, 2 ꢀ H-5, and H-6b), 2.09, 2.00, 1.97, 1.91
(4 ꢀ s, 4 ꢀ 6H, COCH3); 13C NMR (CDCl3, 150 MHz) d 170.4, 169.7,
169.6, 169.5 (C@O), 132.0, 128.3, 124.6 (C6H4), 96.2 (C-1), 87.3,
85.4 (C„C), 69.3 (C-5), 68.9 (C-2), 68.9 (C-3), 65.9 (C-4), 62.1
(C-6), 55.6 (H2CC„C), 20.8, 20.7, 20.5, 20.4 (COCH3); FAB-MS m/z
calcd for C40H46O20 [M+K]+ 885.22, found, 885.38.
3.2.12. 4,40-Bis-(2,3,4,6-tetra-O-acetyl-
a-D-
mannopyranosyloxy)biphenyl (15)
To a solution of 8 (100 mg, 0.182 mmol, 1.00 equiv), tetrabutyl-
ammonium bromide (59 mg, 0.182 mmol, 1.00 equiv), and sodium
acetate (45 mg, 0.458 mmol, 2.52 equiv), in dry DMF (1.8 mL,
0.1 M), was added palladium acetate (4 mg, 0.018 mmol,
0.10 equiv) under nitrogen. The reaction mixture was stirred at
130 °C until complete disappearance of the starting product (4 h).
The reaction mixture was allowed to cool down to room tempera-
ture, then EtOAc (10 mL) was added and the organic layer was
washed with water (3 ꢀ 10 mL), brine (10 mL), and dried over
MgSO4. After concentration under reduced pressure, the brown
crude product was purified by column chromatography (hexane/
EtOAc 1:1) to afford 15 as a yellowish solid (49 mg, 64%); Rf (hex-
3.2.15. 1,2-Bis-[1,10(
ynyl]benzene (22)
a-D
-mannopyranosyloxy)-prop-2,20-
The titled compound was obtained as a yellowish solid by
deacetylation of 21 (0.150 g, 0.018 mmol) using the method de-
scribed above for 4 (0.087 g, quant. yield); mp 92–93 °C; ½a D23
ꢁ
+129.3 (c 1.2, MeOH); 1H NMR (DMSO-d6, 300 MHz) d 7.51 (d,
JH,H 6.4 Hz, 1H, Har), 7.50 (d, JH,H 5.6 Hz, 1H, Har), 7.40 (d, JH,H
5.6 Hz, 1H, Har), 7.38 (d, JH,H 5.5 Hz, 1H, Har), 4.93 (br s, 2H,
2 ꢀ H-1), 4.86 (d, J 4.4 Hz, 2H, 2 ꢀ C-OH), 4.78 (d, J 4.4 Hz, 2H,
2 ꢀ C-OH), 4.65 (d, J 5.5 Hz, 2H, 2 ꢀ C-OH), 4.55 (t, J 4.2 Hz,
2H, 2 ꢀ C-OH), 4.51, 4.49 (2 ꢀ s, 4H, 2 ꢀ H2CC„C), 3.64–3.46 (m,
10H, 2 ꢀ H-2, H-3, H-4, H-5, H-6a, and H-6b); 1H NMR (D2O ex-
change in DMSO-d6, 300 MHz) d 7.51 (d, JH,H 5.2 Hz, 1H, Har),
7.49 (d, JH,H 5.67 Hz, 1H, Har), 7.39 (d, JH,H 5.7 Hz, 1H, Har), 7.38
ane/EtOAc 55:45) 0.19; mp 164–165 °C; ½a D23
ꢁ
+108.7 (c 1, CHCl3);
3
1H NMR (CDCl3, 300 MHz) d 7.48 (d, JH,H 8.8 Hz, 4H, Har), 7.15 (d,
3JH,H 8.8 Hz, 4H, Har), 5.57 (dd, J2,3 3.3 Hz, J3,4 10.2 Hz, 2H,
3
3
3
3
3
2 ꢀ H-3), 5.56 (d, J1,2 1.6 Hz, 2H, 2 ꢀ H-1), 5.48 (dd, J1,2 1.6 Hz,
(d, JH,H 5.3 Hz, 1H, Har), 4.92 (d, J1,2 1.2 Hz, 2H, 2 ꢀ H-1), 4.50,
3J2,3 3.3 Hz, 2H, 2 ꢀ H-2), 5.39 (t, J3,4 = 3J4,5 10.2 Hz, 2H, 2 ꢀ H-4),
4.48 (2 ꢀ s, 4H, 2 ꢀ H2CC„C), 3.70–3.35 (m, 10H, 2 ꢀ H-2, H-3,
3
3
2
4.30 (dd, J5,6a 5.8 Hz, J6a,6b 12.6 Hz, 2H, 2 ꢀ H-6a), 4.15–4.07 (m,
4H, 2 ꢀ H-5, and H-6b), 2.22, 2.07, 2.05, 2.04 (4 ꢀ s, 4 ꢀ 6H,
COCH3); 13C NMR (CDCl3, 75 MHz) d 170.5, 170.0, 169.9, 169.7
(C@O), 154.9, 135.3, 127.9, 116.8 (C6H4), 95.8 (C-1), 69.3, 69.1,
68.8, 65.9, 62.1 (C-2, C-3, C-4, C-5, and C-6), 20.9, 20.7 (COCH3);
H-4, H-5, H-6a, and H-6b); 13C NMR (DMSO-d6, 75 MHz)
d
132.0, 128.9, 124.3 (C6H4), 98.2 (C-1), 89.7, 84.2 (C„C), 74.4,
70.9, 70.2, 70.1, 66.7 (C-2, C-3, C-4, C-5), 61.1, 61.0 (C-6, C-60),
53.6 (CH2); ESI+-MS m/z calcd for C24H30O12 [Mꢂ8(OH)]+ 346.1,
found, 346.8.

M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
1487
3.2.16. 1,3-Bis-[1,10(2,3,4,6-tetra-O-acetyl-
a
-
D
-
NMR (CDCl3, 600 MHz) d 7.43 (dd, JH,H 1.5 Hz, JH,H 7.6 Hz, 2H,
Har), 7.25 (dd, J 1.6 Hz, J 8.5 Hz, 2H, Har), 7.13 (d, JH,H 8.0 Hz, 2H,
Har), 7.07 (ddd, JH,H 0.9 Hz, JH,H 7.6 Hz, JH,H 8.3 Hz, 2H, Har), 5.67
mannopyranosyloxy)prop-2,20-ynyl]benzene (24)
Nitrogen gas was bubbled through a solution of 2-propynyl
3
3
3
2,3,4,6-tetra-O-acetyl-
a-D
-mannopyranoside (11) (1.30 g, 3.30
(dd, J2,3 3.5 Hz, J3,4 10.0 Hz, 2H, 2 ꢀ H-3), 5.64 (d, J1,2 1.6 Hz,
3 3
mmol, 1.00 equiv) and 1,3-diiodobenzene (0.51 g, 1.50 mmol,
0.45 equiv) in DMF–Et3N (13–13 mL) for 25 min. Palladium tetra-
kis triphenylphosphine (Pd(PPh3)4) (0.17 g, 0.14 mmol, 0.04 equiv)
was added and the mixture was stirred under N2 for 5 min. The
reaction mixture was heated to 60 °C and stirred under a stream
of N2 for 4 h after which time the reaction was judged complete
by TLC (hexane/EtOAc 1:1). The reaction mixture was cooled and
dissolved in diethylether/toluene (100 mL/50 mL), then washed
with 2 M HCl (2 ꢀ 150 mL), with saturated NaHCO3 soln
(1 ꢀ 150 mL) and then with H2O (1 ꢀ 150 mL). The crude extract
was then purified by column chromatography in silica gel with
hexane/EtOAc 2:3 as eluent. The title product 24 was obtained as
2H, 2 ꢀ H-1), 5.59 (dd, J1,2 1.8 Hz, J2,3 3.4 Hz, 2H, 2 ꢀ H-2), 5.37
3
(t, J3,4 = 3J4,5 10.0 Hz, 2H, 2 ꢀ H-4), 4.29–4.23 (m, 4H, 2 ꢀ H-5,
3
2
and H-6a), 4.04 (d, J5,6b 5.2 Hz, J6a,6b 10.2 Hz, 2H, 2 ꢀ H-6b),
2.17, 2.01, 1.96, 1.98 (4 ꢀ s, 4 ꢀ 6H, COCH3); 13C NMR (CDCl3,
150 MHz) d 170.4, 169.7, 169.5 (C@O), 155.6, 134.1, 129.6, 123.2,
115.3, 114.9 (C6H4), 96.3 (C-1), 89.7 (C„C), 69.9 (C-3), 69.4 (C-5),
69.3 (C-2), 65.9 (C-4), 62.0 (C-6), 20.8, 20.6, 20.6, 20.6 (COCH3);
FAB-HRMS m/z calcd for
C
42H46O20 [M+K]+ 909.2220, found,
909.2176.
3.2.19. Bis-2-(a-D-mannopyranosyloxy)diphenylacetylene (29)
The titled compound was obtained as a yellowish solid by
a yellow crystalline solid (1.20 g, 88% yield); mp 74–77 °C; ½a D23
ꢁ
deacetylation of 28 (0.041 g, 0.048 mmol) using the method de-
+34 (c 1.0, CHCl3); 1H NMR (CDCl3, 600 MHz) d 7.50 (s, 1H, Har),
7.38 (dd, JH,H 1.43 Hz, JH,H 7.8 Hz, 2H, Har), 7.36 (d, JH,H 7.9 Hz, 1H,
scribed above for 4 (0.025 g, quant. yield); mp 104–108 °C; ½a D23
ꢁ
+3.8 (c 1.0, DMF); IR (DMF): 3545.0 cmꢂ1 1H NMR (DMSO-d6,
;
3
3
Har), 5.35 (dd, J3,2 3.4 Hz, J3,4 10.0 Hz, 2H, 2 ꢀ H-3), 5.28 (t,
300 MHz) d 7.51 (dd, JH,H 1.4 Hz, JH,H 9.0 Hz, 2H, Har), 7.34–7.25
(m, 4H, Har), 7.04 (ddd, JH,H 1.3 Hz, JH,H 8.2 Hz, 2H, Har), 5.50 (s,
2H, 2 ꢀ H-1), 4.11 (br s, 8H, C-OH), 3.94 (d, J 1.65 Hz, 2H, 2 ꢀ H-
2), 3.82 (m, 2H, 2 ꢀ H-3), 3.62, 3.43 (m, 6H, 2 ꢀ H-4, H-5, and H-
6); 13C NMR (DMSO-d6, 75 MHz) d 156.6, 132.9, 130.0, 122.3,
116.5, 113.7 (C6H4), 99.2 (C-1), 88.0 (C„C), 75.2, 70.8, 70.2, 67.0,
66.6 (C-2, C-3, C-4, C-5), 61.0 (C-6); ESI+-MS m/z calcd for
3
3
3J3,4 = 3J4,5 10.0 Hz, 2H, 2 ꢀ H-4), 5.28 (dd, J1,2 2.5 Hz, J2,3 4.3 Hz,
3
4
2H, 2 ꢀ H-2), 5.06 (d, J1,2 1.5 Hz, 2H, 2 ꢀ H-1), 4.46 (d, JH,H
3
2
5.1 Hz, 4H, 2 ꢀ H2CC„C), 4.27 (dd, J5,6a 5.2 Hz, J6a,6b 12.3 Hz,
2H, 2 ꢀ H-6a), 4.11–4.06 (m, 2H, 2 ꢀ H-6b), 4.04–4.01 (m, 2H,
2 ꢀ H-5), 2.13, 2.06, 2.01, 1.96 (4 ꢀ s, 4 ꢀ 6H, COCH3); 13C NMR
(CDCl3, 150 MHz) d 170.5, 169.8, 169.8, 169.6 (C@O), 134.9,
132.0, 128.5, 122.4 (C6H4), 96.2 (C-1), 86.1, 83.9 (C„C), 69.4 (C-2,
C-4), 69.0, 68.9 (C-3, C-5), 66.0 (C-2, C-4), 62.3 (C-6), 55.5
(H2CC„C), 20.8, 20.6, 20.6, 20.6 (COCH3); FAB-HRMS m/z calcd
for C40H46O20 [M+K]+ 885.2220, found, 885.2211.
C
26H30O12 [M+NH4]+ 552.2, found, 552.2.
3.2.20. Bis-3a-(2,3,4,6-tetra-O-acetyl-a-D-
mannopyranosyloxy)diphenylacetylene (30)
Nitrogen gas was bubbled through a solution of 3-ethynylphenyl
3.2.17. 1,3-Bis-[1,10(
ynyl]benzene (25)
a-
D
-mannopyranosyloxy)-prop-2,20-
2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside (14) (0.330 g, 0.74
mmol, 4.93 equiv) and 3-iodophenyl 2,3,4,6-tetra-O-acetyl-
a-D-
The titled compound was obtained as a yellowish solid by
mannopyranoside (10) (0.082 g, 0.15 mmol, 1.00 equiv) in Et3N–
DMF (20–2 mL) for 15 min. Pd(PPh3)4 (0.086 g, 0.0074 mmol,
0.05 equiv) was added and the mixture was stirred under N2 gas
for 5 min. The reaction was continued at 60 °C under a stream of
N2 gas for 24 h. The reaction was judged complete by TLC (hex-
ane/EtOAc 1:1). The reaction mixture was dissolved in CHCl3
(30 mL) and washed with 2 M HCl (3 ꢀ 60 mL), then with saturated
NaHCO3 (2 ꢀ 60 mL) then with H2O (2 ꢀ 60 mL). The organic
extract was dried over anhydrous Na2SO4, filtered, and the solvent
removed under reduced pressure. The concentrate was purified by
column chromatography on silica gel (hexane/EtOAc 1:1). Com-
deacetylation of 24 (0.35 g, 0.42 mmol) using the method de-
scribed above for 4 (0.20 g, quant. yield); mp 65–69 °C; ½a D23
ꢁ
+137.7 (c 1.3, MeOH); 1H NMR (DMSO-d6, 600 MHz) d 7.49 (d,
JH,H 6.5 Hz, 2H, Har), 7.47 (br s, 1H, Har), 7.41 (dd, JH,H 7.1 Hz, JH,H
8.3 Hz, 1H, Har), 4.85 (s, 2H, 2 ꢀ H-1), 4.83 (d, J 4.3 Hz, 2H,
2 ꢀ C2-OH), 4.74 (d, J 5.4 Hz, 2H, 2 ꢀ C4-OH), 4.59 (d, J 6.0 Hz,
2H, 2 ꢀ C3-OH), 4.50 (t, J 6.1 Hz, 2H, 2 ꢀ C6-OH), 4.46 (s, 2H,
2 ꢀ H2CC„C), 3.66 (m, 4H, 2 ꢀ H-2, and H-6a), 3.45 (m, 4H,
2 ꢀ H-3, and H-6b), 3.34 (m, 2H, 2 ꢀ H-5), 3.31–3.22 (m, 2H,
2 ꢀ H-4); 13C NMR (DMSO-d6, 150 MHz) d 134.0, 131.8, 129.3,
122.4 (C6H4), 98.4 (C-1), 85.6, 84.5 (C„C), 74.5 (C-4), 70.9 (C-3),
70.1 (C-2), 66.9 (C-5), 61.2 (C-6), 53.6 (H2CC„C); FAB-HRMS m/z
calcd for C24H30O12 [M+K]+ 549.1374, found, 549.1404.
pound 30 was obtained as
a yellowish crystalline powder
(0.104 g, 80% yield); mp 78–79 °C; ½a D23
ꢁ
+126.0 (c 1.0, CHCl3); 1H
NMR (CDCl3, 600 MHz) d 7.26 (m, 4H, Har), 7.19 (ddd, JH,H 1.1 Hz,
JH,H 2.3 Hz, JH,H 7.7 Hz, 2H, Har), 7.05 (ddd, JH,H 1.0 Hz, JH,H 2.5 Hz,
3
3
3.2.18. Bis-2-(2,3,4,6-tetra-O-acetyl-
a
-D
-
JH,H 8.3 Hz, 2H, Har), 5.53 (dd, J2,3 3.5 Hz, J3,4 10.3 Hz, 2H, 2 ꢀ H-
3
3
3
mannopyranosyloxy)diphenylacetylene (28)
3), 5.51 (d, J1,2 2.00 Hz, 2H, 2 ꢀ H-1), 5.42 (dd, J1,2 1.9 Hz, J2,3
3
Nitrogen gas was bubbled through
a
solution of 2-
3.6 Hz, 2H, 2 ꢀ H-2), 5.33 (t, J3,4 = 3J4,5 10.2 Hz, 2H, 2 ꢀ H-4), 4.26
3
2
ethynylphenyl 2,3,4,6-tetra-O-acetyl-
(0.330 g, 0.74 mmol, 3.89 equiv) and 2-iodophenyl 2,3,4,6-tetra-
O-acetyl- -mannopyranoside (9) (0.100 g, 0.19 mmol, 1.00
a
-D
-mannopyranoside (13)
(dd, J5,6a 6.1 Hz, J6a,6b 12.4 Hz, 2H, 2 ꢀ H-6a), 4.09–4.07 (m, 2H,
2 ꢀ H-5), 4.06–4.04 (m, 2H, 2 ꢀ H-6b), 2.17, 2.03, 2.01, 2.01 (4 ꢀ s,
4 ꢀ 6H, COCH3); 13C NMR (CDCl3, 150 MHz) d 170.5, 169.9, 169.8,
169.7 (C@O), 155.4, 129.6, 126.4, 124.3, 119.3, 117.2, (C6H4), 95.8
(C-1), 89.1 (C„C), 69.3 (C-5), 69.2 (C-2), 68.8 (C-3), 66.0 (C-4),
62.1 (C-6), 20.8, 20.6, 20.6 (COCH3); FAB-HRMS m/z calcd for
a-D
equiv) in Et3N–DMF (20–2 mL) for 15 min. Pd(PPh3)4 (0.012 g,
0.010 mmol, 0.05 equiv) was added and the mixture was stirred
under N2 gas for 5 min and was then stirred at 60 °C under a
stream of N2 gas for 22 h until the reaction was judged complete
by TLC (hexane/EtOAc 1:1). The reaction mixture was dissolved
in CHCl3 (50 mL) and washed with 2 M HCl (3 ꢀ 80 mL), then with
saturated NaHCO3 (2 ꢀ 80 mL) and with H2O (2 ꢀ 80 mL). The or-
ganic extract was dried over anhydrous Na2SO4, filtered, and the
solvent removed under reduced pressure. The concentrate was
purified by column chromatography on silica gel (hexane/EtOAc
1:1). Compound 28 was obtained as a yellowish crystalline powder
C
42H46O20 [M+K]+ 909.2220, found, 909.2027.
3.2.21. Bis-3-( -mannopyranosyloxy)diphenylacetylene (31)
a
-D
The titled compound was obtained as a yellowish solid by
deacetylation of 30 (0.110 g, 0.12 mmol) using the method de-
scribed above for 4 (0.066 g, quant. yield); mp 80–82 °C; ½a D23
ꢁ
+74.0 (c 1.0, DMSO); IR (DMF): 3540 cmꢂ1 1H NMR (DMSO-d6,
;
600 MHz) d 7.33 (dd, JH,H 8.0 Hz, JH,H 7.9 Hz, 2H, Har), 7.25 (dd,
JH,H 1.9 Hz, JH,H 3.6 Hz, 2H, Har), 7.19 (d, JH,H 7.6 Hz, 2H, Har), 7.12
(0.127 g, 80% yield); mp 148–150 °C; ½a D23
ꢁ
+34.0 (c 1.0, CHCl3); 1H

1488
M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
(m, 2H, Har), 5.42 (d, 3J1,2 1.6 Hz, 2H, 2 ꢀ H-1), 5.01 (d, J 4.4 Hz, 2H,
2 ꢀ C2-OH), 4.81 (d, J 5.7 Hz, 2H, 2 ꢀ C4-OH), 4.73 (d, J 6.0 Hz, 2H,
2 ꢀ C3-OH), 4.46 (t, J 5.9 Hz, 2H, 2 ꢀ C6-OH), 3.82 (br s, 2H, 2 ꢀ H-
2), 3.67 (m, 2H, 2 ꢀ H-3), 3.59 (ddd, JOH,6a 5.8 Hz, 3J5,6a 7.8 Hz, 2J6a,6b
11.8 Hz, 2H, 2 ꢀ H-6a), 3.52–3.43 (m, 4H, 2 ꢀ H-5, and H-6b), 3.39
(m, 2H, 2 ꢀ H-4); 13C NMR (DMSO-d6, 150 MHz) d 156.3, 130.0,
123.1, 119.3, 117.9 (C6H4), 98.6 (C-1), 89.1 (C„C), 75.1 (C-4), 70.6
(C-3), 70.0 (C-2), 66.7 (C-5), 61.0 (C-6); FAB-MS m/z calcd for
1:1 then pure EtOAc). The titled compound 36 was obtained as yel-
low crystalline powder (0.078 g, 63% yield); mp 74–76 °C; ½a D23
ꢁ
+5.3
(c 1.2, CHCl3); 1H NMR (CDCl3, 600 MHz) d 7.56 (dd, JH,H 1.8 Hz, JH,H
7.7 Hz, 2H, Har), 7.3 (ddd, JH,H 1.7 Hz, JH,H 8.0 Hz, JH,H 8.4 Hz, 2H, Har),
7.10 (d, JH,H 8.1 Hz, 4H, Har), 7.03 (m, 2H, Har), 5.64 (dd, 3J2,3 3.5 Hz,
3
3J3,4 10.0 Hz, 2H, 2 ꢀ H-3), 5.59 (d, J1,2 1.8 Hz, 2H, 2 ꢀ H-1), 5.55
(dd, 3J1,2 1.9 Hz, 3J2,3 3.5 Hz, 2H, 2 ꢀ H-2), 5.36 (t, 3J3,4 = 3J4,5 9.9 Hz,
2H, 2 ꢀ H-4), 4.30–4.23 (m, 4H, 2 ꢀ H-5, and H-6a), 4.11–4.05 (m,
2H, 2 ꢀ H-6b), 2.17, 2.01, 2.01, 1.99 (4 ꢀ s, 4 ꢀ 6H, COCH3); 13C
NMR (CDCl3, 150 MHz) d 170.04, 169.8, 167.8, 169.4 (C@O), 157.3,
134.5, 130.3, 123.2, 116.0, 113.6 (C6H4), 96.8 (C-1), 79.5, 77.7
(C„C), 69.5 (C-5), 69.4 (C-2), 68.7 (C-3), 65.9 (C-4), 62.1 (C-6),
21.0, 20.5, 20.6, 20.6 (COCH3); FAB-HRMS m/z calcd for C44H46O20
[M+K]+ 933.2220, found, 933.2621.
C
26H30O12 [M+H]+ 535.17, found, 535.12.
3.2.22. Bis-4-(2,3,4,6-tetra-O-acetyl-
mannopyranosyloxy)diphenyl-but-1,3-diyne (34)
4-Ethynylphenyl 2,3,4,6-tetra-O-acetyl- -mannopyranoside
a-D-
a
-D
(12) (0.230 g, 0.52 mmol, 1.00 equiv) and copper(II) acetate
[Cu(OAc)2H2O] (0.011 g, 0.054 mmol, 0.10 equiv) were refluxed in
pyridine (20 mL) under a stream of N2 gas. The reaction was fol-
lowed by TLC on silica gel (hexane/EtOAc 1:1) and was judged
complete after 48 h. The reaction mixture was diluted in CH2Cl2
(40 mL) washed with 2 M HCl (3 ꢀ 80 mL), then with saturated
NaHCO3 (2 ꢀ 80 mL) then with H2O (2 ꢀ 80 mL). The organic layer
was dried over anhydrous Na2SO4, filtered, and the solvent was re-
moved under reduced pressure. The concentrate was purified by
column chromatography on silica gel with hexane EtOAc 1/1 as
eluent. The titled compound 34 was obtained as yellow crystalline
3.2.25. Bis-2-(a-D-mannopyranosyloxy)diphenyl-but-1,3-diyne
(37)
The titled compound was obtained as a white solid by deacety-
lation of 36 (0.070 g, 0.082 mmol) using the method described
above for 4 (0.046 g, quant. yield); mp 130–132 °C; ½a D23
ꢂ0.8 (c
ꢁ
1.3, DMF); IR (DMF): 3544.0 cmꢂ1 1H NMR (DMSO-d6, 500 MHz)
;
d 7.55 (dd, JH,H 1.5 Hz, JH,H 7.7 Hz, 2H, Har), 7.41 (ddd, JH,H 1.6 Hz,
JH,H 8.3 Hz, 2H, Har), 7.30 (d, JH,H 8.4 Hz, 2H, Har), 7.04 (dd, JH,H
7.5 Hz, JH,H 7.4 Hz, 2H, Har), 5.48 (s, 2H, 2 ꢀ H-1), 5.07 (d, J 4.4 Hz,
2H, 2 ꢀ C2-OH), 4.94 (d, J 5.5 Hz, 2H, 2 ꢀ C3-OH), 4.9 (d, J 5.8 Hz,
2H, 2 ꢀ C4-OH), 4.43 (t, J 5.8 Hz, 2H, 2 ꢀ C6-OH), 3.91 (br s, 2H,
2 ꢀ H-2), 3.75 (m, 2H, 2 ꢀ H-3), 3.59 (m, 2H, 2 ꢀ H-6a), 3.55–3.50
(m, 2H, 2 ꢀ H-4), 3.48–3.36 (m, 4H, 2 ꢀ H-5, and H-6a); 13C NMR
(DMSO-d6, 150 MHz) d 158.1, 134.1, 131.3, 122.2, 116.0 (C6H4),
99.1 (C-1), 78.7, 77.2 (C„C), 75.2 (C-5), 70.6 (C-3), 69.9 (C-2),
66.6 (C-4), 61.0 ppm (C-6); ESI+-MS m/z calcd for C28H30O12
[M+H]+ 558.2, found, 558.2.
powder (0.108 g, 47% yield); mp 88–89 °C; ½a D23
ꢁ
+79.0 (c 1.0,
CHCl3); 1H NMR (CDCl3, 600 MHz): d 7.63 (d, JH,H 8.6 Hz, 4H, Har),
3
3
7.06 (d, JH,H 8.7 Hz, 4H, Har), 5.53 (dd, J2,3 3.5 Hz, J3,4 8.0 Hz, 2H,
3
3
2 ꢀ H-3), 5.43 (s, 2H, 2 ꢀ H-1), 5.44 (dd, J1,2 1.8 Hz, J2,3 3.5 Hz,
2H, 2 ꢀ H-2), 5.34 (t, J3,4 = 3J4,5 10.1 Hz, 2H, 2 ꢀ H-4), 4.26 (dd,
3
3J5,6a 5.2 Hz, J6a,6b 12.4 Hz, 2H, 2 ꢀ H-6a), 4.09–4.03 (m, 4H,
2
2 ꢀ H-5, and H-6b), 2.20, 2.05, 2.04, 2.02 (4 ꢀ s, 4 ꢀ 6H, COCH3);
13C NMR (CDCl3, 150 MHz) d 170.4, 169.9, 169.8, 169.6 (C@O),
156.0, 134.1, 116.6 (C6H4), 95.6 (C-1), 80.8, 73.5 (C„C), 69.4 (C-
5), 69.2 (C-2),68.7 (C-3), 65.9 (C-4), 62.0 (C-6), 20.8, 20.6, 20.6
(COCH3); FAB-HRMS m/z calcd for C44H46O20 [M+K]+ 933.2220,
found, 933.1648.
3.2.26. Bis-3-(2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyloxy)
diphenyl-but-1,3-diyne (38)
Compound 14 (0.100 g, 0.22 mmol, 1.00 equiv) and copper(II)
acetate [Cu(OAc)2H2O] (0.0044 g, 0.022 mmol, 0.10 equiv) were re-
fluxed in pyridine (10 mL) under a stream of N2 gas. The reaction
was followed by TLC on silica gel (hexane/EtOAc 1:1) and was
judged complete after 48 h. The reaction mixture was diluted with
CH2Cl2 (30 mL) washed with 2 M HCl (3 ꢀ 60 mL), then with satu-
rated NaHCO3 (2 ꢀ 60 mL) then with H2O (2 ꢀ 60 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and the solvent
was removed under reduced pressure. The concentrate was puri-
fied by silica gel column chromatography using gradient elution
(hexane/EtOAc 2:1 then 1:1). Compound 38 was obtained as yel-
3.2.23. Bis-4-(
(35)
a-D-mannopyranosyloxy)diphenylbut-1,3-diyne
The titled compound was obtained as a yellowish solid by
deacetylation of 34 (0.098 g, 0.12 mmol) using the method de-
scribed above for 4 (0.064 g, quant. yield); mp 163–164 °C; ½a D23
ꢁ
+89.2 (c 1.2, DMF); IR (DMF): 3561.0 cmꢂ1 1H NMR (DMSO-d6,
;
600 MHz) d 7.52 (d, JH,H 8.6 Hz, 4H, Har), 7.11 (d, JH,H 8.7 Hz, 4H,
Har), 5.44 (s, 2H, 2 ꢀ H-1), 5.07 (s, 2H, 2 ꢀ C2-OH), 4.85 (d, J
4.8 Hz, 2H, 2 ꢀ C4-OH), 4.76 (d, J 3.8 Hz, 2H, 2 ꢀ C3-OH), 4.46 (br
s, 2H, 2 ꢀ C6-OH), 3.82 (br s, 2H, 2 ꢀ H-2), 3.66 (dd, J2,3 4.5, J3,4
8.3 Hz, 2H, 2 ꢀ H-3), 3.59–3.45 (m, 4H, 2 ꢀ H-4, H-6a), 3.41 (m,
2H, 2 ꢀ H-6b), 3.34 (m, 2H, 2 ꢀ H-5); 13C NMR (DMSO-d6,
150 MHz) d 157.4, 113.7, 134.0, 117.1 (C6H4), 98.6 (C-1), 81.5,
72.9 (C„C), 75.2 (C-5), 70.6 (C-3), 69.9 (C-2), 66.6 (C-4), 61.0 (C-
6); FAB-MS m/z calcd for C28H30O12 [Mꢂ4OH]+ 486.1, found, 486.2.
low amorphus powder (0.058 g, 58% yield); mp 85–88 °C; ½a D23
ꢁ
3
3
+73.8 (c 2.6, CHCl3); 1H NMR (CDCl3, 600 MHz) d 7.28 (m, 2H,
Har), 7.25 (d, JH,H 8.0 Hz, 2H, Har), 7.21 (ddd, JH,H 1.2 Hz, JH,H
2.5 Hz, JH,H 8.0 Hz, 2H, Har), 7.08 (ddd, JH,H 1.2 Hz, JH,H 2.5 Hz, JH,H
3
3
8.1 Hz, 2H, Har), 5.51 (dd, J2,3 3.5 Hz, J3,4 10.0 Hz, 2H, 2 ꢀ H-3),
3
3
3
5.48 (d, J1,2 1.8 Hz, 2H, 2 ꢀ H-1), 5.41 (dd, J1,2 1.8 Hz, J2,3
3.5 Hz, 2H, 2 ꢀ H-2), 5.32 (t, J3,4 = 3J4,5 10.0 Hz, 2H, 2 ꢀ H-4), 4.25
3
3
2
3.2.24. Bis-2-(2,3,4,6-tetra-O-acetyl-
mannopyranosyloxy)diphenyl-but-1,3-diyne (36)
2-Ethynylphenyl 2,3,4,6-tetra-O-acetyl- -mannopyranoside
a
-D
-
(dd, J5,6a 6.465 Hz, J6a,6b 12.6 Hz, 2H, 2 ꢀ H-6a), 4.12–4.04 (m,
4H, 2 ꢀ H-5, and H-6b), 2.18, 2.04, 2.03, 2.01 (4 ꢀ s, 4 ꢀ 6H,
a
-D
COCH3); 13C NMR (CDCl3, 150 MHz)
d 170.6, 169.9, 169.9,
(13) (0.12 g, 0.27 mmol, 1.00 equiv) and copper(II) acetate
[Cu(OAc)2H2O] (0.0029 g, 0.014 mmol, 0.05 equiv) were refluxed
in pyridine (10 mL) under a stream of N2 gas. Reaction was fol-
lowed by TLC on silica gel (hexane/EtOAc 1:1) and was judged
complete after 24 h. The reaction mixture was diluted in CH2Cl2
(30 mL) washed with 2 M HCl (3 ꢀ 60 mL), then with saturated
NaHCO3 (2 ꢀ 60 mL) and with H2O (2 ꢀ 60 mL). The organic layer
was dried over anhydrous Na2SO4, filtered, and the solvent was
removed in vacuo. The concentrate was purified by column chro-
matography on silica gel using gradient elution (hexane/EtOAc
169.715 (C@O), 155.4, 129.8, 127.4, 123.0, 120.2, 118.3 (C6H4),
95.9 (C-1), 81.1, 74.1 (C„C), 69.3 (C-2 and C-5), 68.8 (C-3), 66.0
(C-4), 62.2 (C-6), 20.8, 20.6, 20.6 (COCH3); FAB-HRMS m/z calcd
for C44H46O20 [M+K]+ 933.2220, found, 933.2387.
3.2.27. Bis-3-(a-D-mannopyranosyl)diphenyl-but-1,3-diyne (39)
The titled compound was as a yellowish solid obtained by
deacetylation of 38 (0.023 g, 0.027 mmol) using the method de-
scribed above for 4 (0.015 g, quant. yield); mp 80–82 °C; ½a D23
ꢁ
+71.0 (c 1.0, DMF); IR (DMF): 3540 cmꢂ1 1H NMR (DMSO-d6,
;

M. Bergeron-Brlek et al. / Carbohydrate Research 346 (2011) 1479–1489
1489
12. Giguère, D.; Sato, S.; St-Pierre, C.; Sirois, S.; Roy, R. Bioorg. Med. Chem. Lett. 2006,
1668–1672.
13. Giguère, D.; Patnam, R.; Bellefleur, M.-A.; St-Pierre, C.; Sato, S.; Roy, R. Chem.
Commun. 2006, 2379–2381.
14. Imberty, A.; Chabre, Y. M.; Roy, R. Chem. Eur. J. 2008, 14, 7490–7499.
15. Tejler, J.; Salameh, B.; Lefflerc, H.; Nilsson, U. J. Org. Biomol. Chem. 2009, 7,
3982–3990.
600 MHz) d 7.35 (dd, JH,H 8.0 Hz, JH,H 8.0 Hz, 2H, Har), 7.29 (br s, 2H,
Har), 7.23 (d, JH,H 7.7 Hz, 2H, Har), 7.18 (ddd, JH,H 1.6 Hz, JH,H 2.4 Hz,
JH,H 8.2 Hz, 2H, Har), 5.39 (d, J1,2 1.6 Hz, 2H, 2 ꢀ H-1), 5.09 (d, J
3
4.4 Hz, 2H, 2 ꢀ C2-OH), 4.87 (d, J 5.7 Hz, 2H, 2 ꢀ C4-OH), 4.71 (d,
J 6.0 Hz, 2H, 2 ꢀ C3-OH), 4.53 (t, J 5.8 Hz, 2H, 2 ꢀ C6-OH), 3.81
(br s, 2H, 2 ꢀ H-2), 3.65 (m, 2H, 2 ꢀ H-3), 3.58 (m, 2H, 2 ꢀ H-6a),
3.41 (m, 4H, 2 ꢀ H-5, and H-6b), 3.36 (m, 2H, 2 ꢀ H-4); 13C NMR
(DMSO-d6, 150 MHz) d 156.3, 130.2, 126.2, 121.4, 120.0, 119.2
(C6H4), 98.9 (C-1), 81.7 (C„C), 75.1 (C-4), 73.3 (C„C), 70.6 (C-3),
69.9 (C-2), 66.7 (C-5), 61.0 (C-6); FAB-HRMS m/z calcd for
16. Sharon, N. FEBS Lett. 1987, 217, 145–157.
17. Touaibia, M.; Roy, R. Mini-Rev. Med. Chem. 2007, 7, 1270–1283.
18. Touaibia, M.; Wellens, A.; Shiao, T. C.; Wang, Q.; Sirois, S.; Bouckaert, J.; Roy, R.
ChemMedChem 2007, 2, 1190–1201.
19. Arya, P.; Kutterer, K. M. K.; Qin, H.; Roby, J.; Barnes, M. L.; Kim, J.-M.; Roy, R.
Bioorg. Med. Chem. Lett. 1998, 8, 1127–1132.
20. André, S.; Liu, B.; Gabius, H.-J.; Roy, R. Org. Biomol. Chem. 2003, 1, 3909–3916.
21. Dam, T. K.; Roy, R.; Pagé, D.; Brewer, C. F. Biochemistry 2002, 41, 1351–1358.
22. Pagé, D.; Roy, R. Bioconjugate Chem. 1997, 8, 714–723.
23. Pagé, D.; Zanini, D.; Roy, R. Bioorg. Med. Chem. 1996, 4, 1949–1961.
24. Pagé, D.; Roy, R. Glycoconjugate J. 1997, 14, 345–356.
25. Dam, T. K.; Oscarson, S.; Roy, R.; Das, S. K.; Pagé, D.; Macaluso, F.; Brewer, C. F. J.
Biol. Chem. 2005, 280, 8640–8646.
26. Dam, T. K.; Roy, R.; Pagé, D.; Brewer, C. F. Biochemistry 2002, 41, 1359–1363.
27. Dam, T. K.; Brewer, C. F. Biochemistry 2008, 47, 8470–8476.
28. Dam, T. K.; Gerken, T. A.; Brewer, C. F. Biochemistry 2009, 48, 3822–3827.
29. Lameignere, E.; Shiao, T. C.; Roy, R.; Wimmerova, M.; Dubreuil, F.; Varrot, A.;
Imberty, A. Glycobiology 2010, 20, 87–98.
C
28H30O12 [M+K]+ 597.1374, found, 597.2025.
Acknowledgments
We are thankful to the Natural Sciences and Engineering Re-
search Council of Canada (NSERC) for partial support of this work
and to FQRNT (Québec) for a scholarship to M.B.-B.
Supplementary data
30. Das, S. A.; Trono, M. C.; Roy, R. Methods Enzymol. 2003, 362, 3–17.
31. Roy, R.; Das, S. K.; Santoyo-González, F.; Hernández-Mateo, F.; Dam, T. K.;
Brewer, C. F. Chem. Eur. J. 2000, 6, 1757–1762.
32. Roy, R.; Das, S. K.; Dominique, R.; Trono, M. C.; Hernández-Meteo, F.; Santoyo-
González, F. Pure Appl. Chem. 1999, 71, 565–571.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2011.03.041.
33. Roy, R.; Trono, M. C.; Giguère, D. ACS Symp. Ser. 2004, 896, 137–150; See also:
Kaufman, R. J.; Sidhu, R. S. J. Org. Chem. 1982, 47, 4941–4947.
34. Sonogashira, K. In Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 203–209.
35. For a review: Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed.
2000, 39, 2632–2657.
References
1. Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 321–327.
2. Roy, R. Trends Glycosci. Glycotechnol. 2003, 15, 291–310.
3. Chabre, Y. M.; Roy, R. Curr. Top. Med. Chem. 2008, 14, 1237–1285.
4. Chabre, Y. M.; Roy, R. In Horton, D., Ed. Adv. Carbohydr. Chem. Biochem. 2010, 63,
165–393.
5. Röckendorf, N.; Lindhorst, T. K. Top. Curr. Chem. 2001, 217, 201–238.
6. Turnbull, W. B.; Stoddart, J. F. Rev. Mol. Biotechnol. 2002, 90, 231–255.
7. Jayaraman, N. Chem. Soc. Rev. 2009, 38, 3463–3483.
36. Giovenzena, G.; Lay, L.; Monti, D.; Palmisano, G.; Panza, L. Tetrahedron 1999, 55,
14123–14136.
37. The reaction time and the yield depend on the ratio
1 (that can vary over 3:1 to pure ). Best yields and faster reactions are
obtained when the anomeric configuration is (ex: pure, 12 h, 95%).
a/b of the starting material
a
a
a
38. Mereyala, H. B.; Gurrala, S. R. Carbohydr. Res. 1998, 307, 351–354.
39. Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133–173.
40. Yu, M.; Tang, R.-Y.; Li, J.-H. Tetrahedron 2009, 65, 3409–3416.
41. Hay, A. S. J. Org. Chem. 1962, 27, 3320–3321.
8. Pieters, R. J. Trends Glycosci. Glycotechnol. 2004, 16, 243–254.
9. Pieters, R. J.; Liskamp, R. M. J. Anti-Infect. Agents Med. Chem. 2008, 7, 193–200.
10. Pieters, R. J. Org. Biomol. Chem. 2009, 7, 2013–2025.
11. Touaibia, M.; Roy, R. Application of Multivalent Mannosylated Dendrimers in
Glycobiology. In Comprehensive Glycoscience; Kamerling, J. P., Ed.; Carbohydrate–
Protein and Carbohydrate–Carbohydrate Interactions; Elsevier: Oxford, 2007;
Vol. 3, pp 821–870. Chapter 3.36.
42. André, S.; Giguère, D.; Dam, T. K.; Brewer, C. F.; Gabius, H.-J.; Roy, R. New J.
Chem. 2010, 34, 2229–2240.