New synthesis of mannoside-containing neoglycoconjugates by reaction of propargyl mannosides with polyalkylcarboxylated scaffolds

Article abstract of DOI:10.1055/s-2005-861828

A new, efficient and easy synthesis of multivalent mannoside neoglyconjugates is described by the alkynylation reaction of lithium acetylides derived from adequately protected propargyl α-D-mannoside and readily available polyalkylcarboxylate benzene derivatives as scaffolds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-861828

PAPER
939
New Synthesis of Mannoside-Containing Neoglycoconjugates by Reaction of
Propargyl Mannosides with Polyalkylcarboxylated Scaffolds
S
ynthesis of Ma
n
l
noside
o
Containing G
t
lycoco
i
njugat
l
es from
d
Propargyl
M
e
annosides Ferrandiz-Huertas, Joaquín Isac-García, Francisco Pérez-Balderas, Francisco Santoyo-González*
Instituto de Biotecnología, Departamento de Química Orgánica, Facultad de Ciencias, Campus Fuentenueva s/n, Universidad de Granada,
Granada, 18071, Spain
Fax +34(958)243187; E-mail: fsantoyo@ugr.es
Received 24 September 2004; revised 17 December 2004
nogashira-type cross-coupling reaction of alkynyl glyco-
Abstract: A new, efficient and easy synthesis of multivalent man-
sides,8j,l,9b,10 the cyclotrimerization of terminal as well as
noside neoglyconjugates is described by the alkynylation reaction
of lithium acetylides derived from adequately protected propargyl
a-D-mannoside and readily available polyalkylcarboxylate benzene
derivatives as scaffolds.
symmetrical alkyne sugar derivatives mediated by transi-
tion metal catalysts11 and, more recently, the alkyne-azide
cycloaddition reaction catalyzed by Cu(I).8m In our con-
tinuing efforts towards rational design and efficient syn-
thesis of multivalent neoglycoconjugates, we now
describe that propynyl glycosides are also adequate sub-
strates for the construction of a-D-mannoside clusters by
reaction of the corresponding lithium acetylides with
polyalkylcarboxylates.
Key words: glycosides, neoglycoconjugates, clusters, alkynes,
polyalkylcarboxylates
Protein-carbohydrate recognition events mediate signifi-
cant biological processes including fertilization, patho-
gen-cell adhesion, and the inflammatory response.1
Multivalency in ligand-receptor interactions is an impor-
tant principle used by nature to increase weak interactions
to biologically relevant levels.2 Following this observa-
tion and with the expectation of understanding the molec-
ular details of a such process and to therapeutically
manipulate these interactions, synthetic glycoligands or
neoglycoconjugates3 have emerged as valuable tools.
They also bear other potential advantages such as a great-
er flexibility for the introduction of structural modifica-
tions. Many such compounds have been constructed based
on the so-called cluster glycoside effect4 in order to mimic
the multivalency and to improve their stability, specifici-
ty, and affinity.
The nucleophilic addition of alkynyl organomethallic re-
agents to unsaturated C=X systems (X = O, NR) is a very
convenient and reliable strategy for carbon-carbon bond
formation that has not been used as extensively as other
organometallic nucleophilic addition to those systems.12
However, to the best of our knowledge there are prece-
dents for reactivity of metal acetylides with esters only.
Hess et al.13a reported the first reaction of alkynyl Grig-
nard with ethyl benzoate. By application of this reaction,
geminal bis(alkynyl)carbinols has been prepared.13b,14
Young et al.15 have reported that the reaction of tosyl-N-
aziridine-2-carboxylate esters with lithium trimethylsilyl-
acetylide led to the corresponding tertiary alcohol. In ad-
dition, other work has also indicated that Grignard and
non-acetylenic organolithium reagents attack the ester
function in such aziridines.16 On the other hand, the hy-
droalumination of bis-alkynyl alcohols has been
reported17 as a novel route for the synthesis of stereogenic
tertiary alcohol centers. Finally, tetrakis-alkynyl diols
have been synthesized as modules for acetylenic molecu-
lar scaffolding.18
As terminal mannoside residues have been found to inter-
act with receptors found on macrophages,5 hepatical sinu-
soidal cells6 and different invading pathogens,7 numerous
efforts have been devoted to the synthesis of mannoside
neoglyconjugates for the study of mannoside receptor in-
teractions and their potential application as inhibitors of
pathogenic infections and targeting devices.8
Taking into consideration all this precedents, we thought
that a-D-mannoside could be easily grafted onto aromatic
cores by using polyalkylcarboxylate benzene derivatives
readily accessible from commercial sources and acetyl-
ides derived from propargyl mannosides (see Scheme 1).
In search of new methodologies for the synthesis of
neoglyconjugates we and others have recently contributed
by introducing the use of propynyl glycosides as versatile
and efficient synthons for the construction of multivalent
systems with a well defined architecture. The particular
and characteristic reactivity of the acetylenic function
have found notable applications through a variety of dif-
ferent strategies such as the oxidative dimerization of pro-
pynyl glycopyranosides with palladium and copper-
catalyzed homo- and cross-coupling reactions,8k,9 the So-
O-Man
Man
O
OH
(COOR)n
BuLi
Core
Core
O-Man
n
SYNTHESIS 2005, No. 6, pp 0939–0944
Advanced online publication: 21.02.2005
DOI: 10.1055/s-2005-861828; Art ID: T10904SS
x
x
.
x
x
.2
0
0
5
Scheme 1 Strategy for the synthesis of mannoside neoglycoconju-
gates
© Georg Thieme Verlag Stuttgart · New York

940
C. Ferrandiz-Huertas et al.
PAPER
O
O
Aromatic cores are particularly attractive since the pres-
ence of an aromatic heterocyclic group next to the glyco-
side bond has been shown to contribute positively to the
interaction of neoglycoconjugates with lectins by increas-
ing the hydrophobicity.8a,19 In addition, the particular to-
pology of the resulting structures should confer a high
rigidity to the neoglycoconjugates diminishing the entrop-
ic loss that is usually associated with flexible and hydrated
carbohydrate ligands. Better inhibitory properties than
AcO
AcO
O
O
1) NaOMe, MeOH
O
O
2) 2,2-Dimethoxypropane,
camphor-10 sulfonic acid,
acetone, 73%
O
O
AcO
OAc
1
2
Scheme 2 Synthesis of propargylated mannoside synthon
those of their more flexible counterparts could be expect- yields (see Table 1). O-Deprotection of these compounds
ed, as was previously observed.8j,k
was performed by acid hydrolysis using HOAc–H2O
yielding the corresponding hydroxylated derivatives 9,
11, 13, 15, and 17, respectively.
For the preparation of acetylides derived from propargyl
mannosides, we synthesized 2-propynyl 2,3:4,6-di-O-iso-
propylidene-a-D-mannopyranoside 2 as the most appro- The various hydroxylated mannose neoglyconjugates 9,
priate synthon considering the tolerance of the O- 11, 13, 15, and 17 were then evaluated for their relative
protective group toward the alkynylation required condi- binding inhibitory properties against peroxidase-labeled
tions and its easy accessibility. Thus, compound 2 was Concavalin A (Con A) lectin. The glycoconjugates were
readily prepared from propargyl 2,3,4,6-tetra-O-acetyl-a- used to inhibit the lectin binding to Saccharomices cere-
D-mannopyranoside 120 in two steps by a conventional visiae mannan that was used as a coating material in com-
Zemplen O-deacetylation followed by subsequent O-iso- petitive solid-phase microtiter plate assays. Triplicate
propylidination (see Scheme2).
results were used for the construction of the inhibition
curves. The results expressed as the IC50 values and when
compared with the low-affinity inhibitor methyl a-D-man-
nopyranoside (see Table 2) indicated a Con A affinity en-
hacement for the hexavalent mannoside 17 relative to
methyl a-D-mannopyranoside (4.53-fold). For the tetrava-
lent mannosides 13 and 15 the Con A affinities were lower
as compared with compound 17. In these compounds a
higher affinity was observed for compound 13 having a
1,4-subsitution pattern for the benzene ring.
Methyl benzoate (3), dimethyl 1,4- and 1,3-benzenedicar-
boxylate (5 and 6, respectively) and trimethyl 1,3,5-ben-
zenetricarboxylate (7) were chosen as readily available
polyalkylcarboxylate aromatic derivatives (see Table 1).
The known ethyl (p-tert-butylphenoxy)acetate (4)21 was
prepared by O-alkylation of p-tert-butyl phenol with ethyl
bromoacetate (see experimental). The alkynylation reac-
tions were performed following standard procedures for
the formation and reaction of lithium acetylides.22 The re-
actions proceeded smoothly leading to the O-protected di-
valent (8 and 10), tetravalent (12 and 14) and hexavalent
(16) mannoside neoglycoconjugates in good to high
Table 1 Synthesis of Multivalent Mannoside Neoglycoconjugates
Core
Neoglycoconjugate (yield)
OR1
R1O
R2O
COOMe
O
O
OH
O
OR2
OR1
O
R2O
R1O
OR2
3
8a R1 = R2 = Me2C (98%)
9b R1 = R2 = H (95%)
OR1
OR2
R1O
R2O
COOEt
O
O
O
OH
O
O
R2O
OR1
R1O
OR2
CH2
O
4
10a R1 = R2 = Me2C (95%)
11b R1 = R2 = H (97%)
Synthesis 2005, No. 6, 939–944 © Thieme Stuttgart · New York

PAPER
Synthesis of Mannoside Containing Glycoconjugates from Propargyl Mannosides
941
Table 1 Synthesis of Multivalent Mannoside Neoglycoconjugates (continued)
Core
Neoglycoconjugate (yield)
OR1
OR2
R1O
R2O
R1O
COOMe
O
O
OH
O
O
R2O
OR1
OR2
COOMe
5
R2O
OR1
OR2
R1O
R2O
R1O
OR2
O
O
OH
O
O
OR1
12a R1 = R2 = Me2C (67%)
13b R1 = R2 = H (93%)
OR1
OR2
MeOOC
R1O
R2O
R1O
COOMe
O
O
O
O
6
R2O
OH
OR1
OR2
HO
R2O
OR1
OR2
OR1
R1O
OR2
R2O
R1O
O
O
O
O
14a R1 = R2 = Me2C (98%)
15b R1 = R2 = H (96%)
R1O
R2O
COOMe
OR1
OR2
MeOOC
O
O
O
O
COOMe
R2O
OH
OR1
R1O
OR2
HO
7
R2O
OR1
R1O
OR2
OR2
OR1
R2O
R1O
O
O
O
O
OH
OR2
OR2
R1O
R2O
O
OR1
OR2
OR1
O
O
O
R1O
16a R1 = R2 = Me2C (76%)
17b R1 = R2 = H (92%)
a Reagents and conditions: (i) 2, BuLi, THF; (ii) 3, 4, 5, 6, or 7, r.t.
b Reagents and conditions: HOAc–H2O (70%), r.t.
The divalent neoglyconjugate 9 showed an IC50 value in nyl glycosides as versatile synthons in the preparation of
the same order as that for the methyl a-D-mannopyrano- neoglycoconjugates. For the compounds prepared in the
side. However, the divalent mannoside 11 showed a sig- present work, aromatic scaffolds were used and the result-
nificant decrease in relative potency when compared to ing neoglycoconjugates evaluated for their relative bind-
methyl a-D-mannopyranoside.
ing properties toward the natural binding plant lectin
Concanavalin A showing good inhibitory properties.
In conclusion, we have demonstrated that multivalent
neoglyconjugates containing mannose as sugar moieties
can be easily prepared by the reaction of lithium acetyl-
ides derived from adequately protected propargyl manno-
sides with polyalkylcarboxylated scaffolds. The
methodology is efficient and broadens the utility of propy-
TLC was performed on Merck silica gel 60F245 aluminum sheets
with detection by charring with sulfuric acid and by UV light when
applicable. Flash column chromatography was carried out on silica
gel, Merck or Scharlau (230–400 mesh. ASTM), with the solvent
systems indicated. All the concentrations were carried out under re-
Synthesis 2005, No. 6, 939–944 © Thieme Stuttgart · New York

942
C. Ferrandiz-Huertas et al.
PAPER
Table 2 ELLA Data for Binding Inhibition of HRP-Labeled Con A by Multivalent Mannoside Neoglycoconjugates
Parameter
Compound
Me-O-Man
9
11
13
15
17
IC50 (mM)
0.68
1
0.85
0.80
0.2
1.77
0.45
0.23
0.26
2.62
0.65
0.47
1.44
0.36
0.15
4.53
0.76
Rel. Potency
Rel. Potencya
1
a Per mol of mannopyranosyl residue relative to methyl a-D-mannopyranoside.
duced pressure at 40 °C. Optical rotations were measured at 22 °C.
Melting points are uncorrected. NMR spectra were recorded at r.t.
1H NMR chemical shifts are given in ppm and referenced to internal
CHCl3 (d = 7.26 ppm) for CDCl3 solutions. 13C NMR chemical
shifts are given in ppm and referenced to CDCl3 (d = 77.0 ppm).
J values are given in Hz. Assignments were based on COSY,
HMQC, NOESY, and DEPT. FAB MS were obtained using m-ni-
trobenzyl alcohol or thioglicerol as the matrix. Anhydrous solvents
were prepared according to standard procedures and were freshly
distilled prior to use. Methyl a-D-mannopyranoside, peroxidase-la-
beled Concavalin A (Con A) lectin and Saccharomices cerevisiae
mannan were purchased from Sigma.
61.8 (C-5), 54.4 (CH2O), 29.1, 28.2, 26.2, 18.8 [2 × C(CH3)2].
Anal. Calcd for C15H22O6: C, 60.39, H, 7.43. Found: C, 60.77, H,
7.80.
Ethyl p-tert-Butylphenyloxyacetate (4)
To a solution of p-tert-butyl phenol (2 g, 13.3 mmol) and ethyl bro-
moacetate (10 mL, 40 mmol) in anhyd CH3CN (15 mL) was added
anhyd K2CO3 (3.7 g, 26.4 mmol). The reaction was kept at r.t. for
18 h. Filtration was followed by evaporation under vacuum of the
solvent giving a residue that was purified by column chromatogra-
phy (CHCl3–hexane, 1:1) and gave 4 (2.74 g, 87.3%) as a liquid.
1H NMR (300 MHz, CDCl3): d = 7.31(d, 2 H, J = 8.8 Hz), 6.85 (d,
2 H, J = 8.8 Hz), 4.60 (s, 2 H), 4.27 (q, 2 H, J = 7.1 Hz), 1.30 (s, 9
H), 1.30 (t, 3 H, J = 7.1 Hz).
Enzyme-Linked Lectin Assay (ELLA)
ELLA assays were carried out as previously described.23 Experi-
ments were carried out using a Metertech S960 instrument. Microti-
tration plates were coated with S. cerevisiae mannan at 100 mL/well
of a solution containing 10 mg/mL in 10mM phosphate buffer (PBS,
pH 7.4) for 2 h at 37 °C. The wells were then washed twice with 10
mM phosphate buffer containing 1% (v/v) Tween 20 (PBST) and
once with PBS. This washing procedure was repeated after each in-
cubation period. Wells were then blocked with 300 mL/well of BSA/
PBS (1% w/v) for 2 h at 37 °C. Each inhibitor was added in serial
dilutions (60 mL/well) to the glycoclusters 9, 11, 13, 15, and 17 or
methyl a-D-mannopyranoside in PBS (pH 6.8, containing 0.1 mM
Ca2+and 0.1 mM Mn2+) and the peroxidase-labeled Con A (60 mL/
well of a solution of 50 mg/mL in PBS, pH 6.8, containing 0.1 mM
Ca2+and 0.1 mM Mn2+) was added. The mixtures of glycoclusters or
methyl a-D-mannopyranoside and the peroxidase-labeled lectin
(100 ml/well) were added and the plates were incubated for 2 h at 37
°C. After that, 50mL/well of a solution of o-phenylenediamine dihy-
drochloride (20 mg/50 mL) in citrate–phosphate buffer (pH 5.0 with
0.4% H2O2) was added. The plates were incubated for 30 min at 37
°C. The reactions were stopped by the addition of aq H2SO4 (50 mL/
well, 1.25 M) and the absorbance measured at 492 nm.
13C NMR (75 MHz, CDCl3): d = 169.1, 155.6, 144.4, 126.3, 114.1,
65.6, 61.2, 34.1, 31.5, 14.1.
Compounds 8, 10, 12, 14, and 16; General Procedure
BuLi (1.6 M in hexane, 4.5 mL, 6.4 mmol) was added to a cooled
(0 °C) solution of 2 (2.0 g, 6.71 mmol) in anhyd THF (10 mL) and
the reaction was stirred under argon at 0 °C for 1 h. The correspond-
ing ester [methyl benzoate (3), ethyl p-tert-butylphenyloxyacetate
(4), dimethyl terephthalate (5), dimethyl isophthalate (6), or 1,3,5-
trimethoxycarbonylbenzene (7)] (0.84 mmol) in THF (4.5 mL) was
then added. The reaction was allowed to warm to r.t. and left under
argon for 24 h. The reaction was cooled to 0 °C and quenched by the
addition of sat. aq NH4Cl (50 mL). The layers were separated and
the aqueous phase was extracted with EtOAc (2 × 50 mL). The
combined organic layers were dried (Na2SO4) and the solvent was
removed in vacuo to yield a crude product that was purified by col-
umn chromatography on silica gel.
4-Phenyl-1,7-bis-O-[2,3:4,6-di-O-isopropylidene-a-D-mannopy-
ranosyl]hep-2,5-diyn-1,4,7-triol (8)
Column chromatography (Et2O–hexane, 1:1) gave 8 (0.58 g,
98.5%) as a solid: mp 96–97 °C; [a]D +61 (c 1, CHCl3).
IR (KBr): 3415, 3428, 1390, 1224, 1079, 859 cm–1.
2-Propynyl 2,3:4,6-Di-O-isopropylidene-a-D-mannopyranoside
(2)
A solution of 2-propynyl a-D-mannopyranoside24 (3.33 g, 15.7
mmol) in anhyd acetone (50 mL), 2,2-dimethoxypropane (10 mL),
and camphor-10-sulfonic acid (25 mg) was kept at r.t. for 24 h. Ad-
dition of Et3N was followed by evaporation and purification of the
crude product by column chromatography (hexane–Et2O, 3:1) to
give 2 (3.31 g, 73%) as a solid; mp 96–98 °C; [a]D +45 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.75 (m, 2 H), 7.37 (m, 3 H), 5.20,
5.18 (2 s, 2 H), 4.34 (s, 4 H), 4.17 (dd, 2 H, J = 7.3, 5.7 Hz), 4.13
(d, 2 H, J = 5.7 Hz), 3.92 (dd, 1 H, J = 10.7, 5.6 Hz), 3.90 (dd, 1 H,
J = 10.6, 5.6 Hz), 3.74 (br t, 2 H, J = 10.0 Hz), 3.74 (dd, 2 H,
J = 10.0, 7.5 Hz), 3.65–3.55 (m, 2 H), 3.13 (s, 1 H), 1.55, 1.51, 1.42,
1.35 (4 s, 24 H).
13C NMR (75 MHz, CDCl3): d = 141.3, 128.8, 128.6, 125.7, 109.5,
99.8, 97.0, 96.8, 86.6, 86.5, 80.3, 80.2, 75.8, 74.7, 72.8, 72.6, 64.8,
61.8, 54.8, 54.7, 29.0, 28.2, 26.2, 18.8.
IR (KBr): 3259, 2126, 1381, 1268, 1220, 1090, 1044, 853 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.24 (s, 1 H, H-1), 4.25 (d, 2 H,
J = 2.4 Hz, CH2C≡), 4.20 (d, 1 H, J = 5.7 Hz, H-2), 4.15 (dd, 1 H,
J = 7.6, 5.7 Hz, H-3), 3.89 (dd, 1 H, J = 10.7, 5.6 Hz, H-6), 3.76 (t,
1 H, J = 10.4 Hz, H-6¢), 3.75 (dd, 1 H, J = 10.0, 7.7 Hz, H-4), 3.58
(dt, 1 H, J = 10.1, 5.6 Hz, H-5), 2.47 (t, 1 H, J = 2.4 Hz, C≡CH),
1.56, 1.52, 1.43 and 1.36 (4 s, 12 H, CMe2).
HMRS (FAB): m/z calcd for C37H48O13Na (M + Na)+, 723.2993;
found, 723.2984.
Anal. Calcd for C37H48O13: C, 63.42, H, 6.90. Found: C, 63.93, H,
7.42.
13C NMR (75 MHz, CDCl3): d = 109.6 (CMe2), 99.8 (CMe2), 96.5
(C-1), 75.9 (C-2), 75.1 (C≡CH), 74.8 (C-3), 72.6 (C-4), 62.0 (C-6),
Synthesis 2005, No. 6, 939–944 © Thieme Stuttgart · New York

PAPER
Synthesis of Mannoside Containing Glycoconjugates from Propargyl Mannosides
943
1,7-Bis-O-[2,3:4,6-di-O-isopropylidene-a-D-mannopyranosyl]
4-(p-4-tert-butylphenyloxymethyl)-hep-2,5-diyn-1,4,7-triol (10)
Column chromatography (Et2O–hexane, 3:1) of the crude gave 10
(0.63 g, 95%) as a solid; mp 58–60 °C; [a]D +36 (c 1, CHCl3).
1,3,5-Tris-[1,7-di-O-(2,3:4,6-di-O-isopropylidene-a-D-man-
nopyranosyl)hep-2,5-diyn-1,4,7-triol-4-yl]benzene (16)
Column chromatography (Et2O–hexane, 3:1) of the crude gave 16
(1.48 g, 76%) as a solid; mp 128–131 °C; [a]D +36 (c 1, CHCl3).
IR (KBr): 3422, 1373, 1220, 1116, 1079, 1043, 1023, 859 cm–1.
IR (KBr): 3422, 1514, 1460, 1383, 1254, 1084, 1022, 860 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32 (d, 2 H, J = 8.8Hz), 6.93 (d,
2 H, J = 8.8Hz), 5.21, 5.20 (2 s, 2 H), 4.30 (s, 2 H), 4.21–4.12 (m,
8 H, H-2,3), 3.94 (dd, 1 H, J = 10.6, 5.4 Hz), 3.93 (dd, 1 H,
J = 10.6, 5.4 Hz), 3.76 (br t, 2 H, J = 10.5 Hz), 3.75 (dd, 2 H,
J = 10.0, 7.5 Hz), 3.65–3.56 (m, 2 H), 3.28 (s, 1 H), 1.56, 1.52, 1.43,
1.36 (4 s, 24 H), 1.30 (s, 9 H).
1H NMR (300 MHz, CDCl3): d = 8.2 (s, 3 H), 5.20 (s, 6 H), 4.45–
4.3 (m, 15 H), 4.20–4.14 (m, 12 H), 3.9–3.5 (m, 24 H), 1.55, 1.50,
1.43, 1.36 (4 s, 72 H).
13C NMR (75 MHz, CDCl3): d = 143.3, 123.8, 109.7, 99.9, 97.2,
97.0, 86.3, 86.1, 80.9, 80.7, 75.9, 74.8, 72.6, 61.8, 61.7, 64.7, 55.1,
54.9, 29.1, 28.3, 26.3, 18.9.
1H NMR (400 MHz, DMSO-d6): d = 7.28 (d, 2 H, J = 8.8 Hz), 6.92
(d, 2 H, J = 8.8 Hz), 6.88 (s, 1 H), 5.21 (s, 2 H), 4.35 (AB system,
4 H, J = 16.2 Hz, Dd = 18 Hz), 4.15 (d, 2 H, J = 5.6 Hz), 4.03 (br s,
2 H), 4.00 (dd, 2 H, J = 8.0, 5.7 Hz), 3.92 (dt, 2 H, J = 10.0, 5.3 Hz),
3.71–3.65 (m, 4 H), 3.40 (dt, 2 H, J = 10.1, 5.5 Hz), 1.45, 1.44, 1.30,
1.29 (4 s, 24 H), 1.25 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 155.9, 144.4, 126.2, 114.7, 109.5,
99.7, 96.8, 96.7, 84.0, 79.9, 79.8, 75.8, 74.7, 72.6, 62.7, 61.8, 54.6,
54.5, 34.1, 31.5, 29.0, 28.2, 26.2, 18.8.
HMRS (FAB): m/z calcd for C99H132O39Na (M + Na)+, 1968.828;
found, 1968.831.
Anal. Calcd for C99H132O39: C, 61.10; H, 6.84. Found: C, 61.17; H,
7.42.
Synthesis of the Hydroxylated Derivatives 9, 11, 13, 15, and 17;
General Procedure
The corresponding glycocluster (8, 10, 12, 14, or 16, 0.075 mmol)
was suspended in HOAc (70%, 5 mL). The reaction mixture was
kept at r.t. under magnetic stirring for 12 h. After this time the sol-
vent was removed in vacuo and the crude product was coevaporated
with H2O (3 × 5 mL). The crude product was then dissolved in H2O
(5 mL) and the solution was concentrated by liophilitation. The cor-
responding deprotected compounds (9, 11, 13, 15, and 17) were iso-
lated in almost quantitative yields.
HMRS (FAB): m/z calcd for C42H58O14Na (M + Na)+, 809.3724;
found, 809.3736.
Anal. Calcd for C42H58O14: C, 64.11; H, 7.43. Found: C, 64.41; H,
7.53.
1,4-Bis-[1,7-di-O-(2,3:4,6-di-O-isopropylidene-a-D-mannopyra-
nosyl)hep-2,5-diyn-1,4,7-triol-4-yl]benzene (12)
Column chromatography (Et2O–hexane, 3:1) of the crude gave 12
(0.75 g, 67.5%) as a solid; mp 140–141 °C; [a]D 34 (c 1, CHCl3).
IR (KBr) 3417, 1460, 1383, 1221, 1076, 1043, 860 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.80 (s, 4 H), 5.17 (s, 4 H), 4.40–
4.28 (m, 8 H), 4.20–4.11 (m, 8 H), 3.80–3.50 (m, 18 H), 1.55, 1.51,
1.43, 1.36 (4 s, 48 H).
13C NMR (75 MHz, CDCl3): d = 142.1, 126.2, 109.7, 99.9, 97.4,
86.1, 80.7, 75.9, 74.9, 72.7, 64.8, 61.9, 55.1 (CH2C≡CH), 29.1,
28.4, 26.3, 18.9 [C(CH3)2].
4-Phenyl-1,7-bis-O-[a-D-mannopyranosyl]hep-2, 5-diyn-1,4,7-
triol (9)
Syrup; [a]D +51 (c 1, pyridine).
IR (KBr): 3399, 1069, 975, 815, 760, 697 cm–1.
13C NMR (75 MHz, D2O): d = 137.3, 130.5, 130.3, 127.2, 100.7,
88.5, 82.5, 74.7, 72.0, 71.5, 67.9, 62.1, 56.2.
MS (FAB): m/z calcd for C25H32O13Na (M + Na)+, 563.1741; found,
563.1741.
1,7-Bis-O-[a-D-mannopyranosyl]4-(p-4-tert-butylphenyloxy-
methyl)hep-2,5-diyn-1,4,7-triol (11)
Syrup; [a]D +135 (c 1, pyridine).
HMRS (FAB): m/z calcd for C68H90O26Na (M + Na)+, 1345.5618;
found, 1345.564.
13C NMR (75 MHz, D2O): d = 156.1, 144.0, 126.2, 114.9, 99.3,
98.7, 84.2, 84.1, 80.3, 73.1, 70.6, 70.4, 70.0, 69.9, 66.6, 66.4, 61.0,
62.1, 60.8, 54.7, 54.5, 54.4, 33.7, 31.3.
HRMS: m/z calcd for C30H42O14Na (M + Na)+, 649.2472; found,
649.2473.
Anal. calcd for C68H90O26: C, 61.71; H, 6.85. Found: C, 61.85; H,
6.95.
1,3-Bis-[1,7-di-O-(2,3:4,6-di-O-isopropylidene-a-D-mannopyra-
nosyl)hep-2,5-diyn-1,4,7-triol-4-yl]benzene (14)
Column chromatography (Et2O–hexane, 1:1) of the crude gave 14
(1.09 g, 98%) as a solid; mp 130–131 °C; [a]D +30 (c 1, CHCl3).
1,4-Bis-[1,7-di-O-a-D-mannopyranosyl)hep-2,5-diyn-1,4,7-tri-
ol-4-yl]benzene (13)
IR (KBr): 3421, 1383, 1221, 1089, 1043, 859 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25 (t, 1 H, J = 1.7 Hz), 7.75 (dd,
2 H, J = 1.8, 7.8 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 5.18, 5.17 (2 s, 4 H),
4.37 (AB system, 4 H, J = 16 Hz, Dd = 27.0 Hz), 4.36 (AB system,
4 H, J = 15.9 Hz, Dd = 19.0 Hz), 4.21 (s, 2 H), 4.19 (d, 4 H, J = 5.7
Hz), 4.15 (dd, 4 H, J = 11.8, 5.7 Hz), 3.83 (dd, 4 H, J = 10.6, 5.1
Hz), 3.74–3.56 (m, 12 H), 1.55, 1.51, 1.50, 1.44, 1.42, 1.36, 1.34 (7
s, 48 H).
Solid; mp 158 °C; [a]D +10 (c 1, pyridine).
IR (KBr): 3420, 1261, 1097, 1022, 801 cm–1.
13C NMR (75 MHz, D2O): d = 142.13, 126.4, 99.6, 85.9, 81.4, 73.4,
70.8, 70.3, 66.7, 64.2, 60.9, 55.1.
HRMS (MALDI-TOF): m/z calcd for C44H58O26Na, 1025.3114;
found, 1025.332 (M + Na)+.
13C NMR (75 MHz, CDCl3): d = 142.1, 129.0, 126.6, 122.6, 109.7,
99.9, 97.4, 97.1, 86.4, 86.2, 80.9, 80.5, 75.9, 74.8, 72.6, 61.9, 61.8,
64.9, 65.9, 55.3, 54.9, 29.1, 28.3, 26.2, 18.9.
HMRS (FAB): m/z calcd for C68H90O26Na (M + Na)+, 1345.5618;
found, 1345.5629.
1,3-Bis-[1,7-di-O-a-D-mannopyranosyl)hep-2,5-diyn-1,4,7-tri-
ol-4-yl]benzene (15)
Solid; mp 200 °C (dec); [a]D +52 (c 1, pyridine).
IR (KBr): 3390, 1561, 1423, 1060, 811, 671 cm–1.
13C NMR (75 MHz, D2O): d = 141.9, 129.9, 126.8, 123.1, 99.7,
85.9, 81.6, 73.4, 70.8, 70.3, 66.7, 64.4, 60.9, 55.1.
HRMS FAB (pos.): m/z calcd for C44H58O26Na (M + Na)+,
Anal. Calcd for C68H90O26: C, 61.71; H, 6.85. Found: C, 61.76; H
6.87.
1025.3114; found, 1025.322.
Synthesis 2005, No. 6, 939–944 © Thieme Stuttgart · New York

944
C. Ferrandiz-Huertas et al.
PAPER
1,3,5-Tris-[1,7-di-O-(a-D-mannopyranosyl)hep-2,5-diyn-1,4,7-
triol-4-yl]benzene (17)
Solid; mp 137 °C; [a]D +5.6, [a]436 +13.0 (c 1, pyridine).
IR (KBr): 3410, 1439, 1379, 1246, 1070, 811 cm–1.
13C NMR (75 MHz, CDCl3): d = 142.9, 124.0, 99.8, 85.5, 82.0, 73.4,
70.8, 70.3, 66.7, 64.3, 60.9, 55.2.
García, J.; Santoyo-González, F. Org. Lett. 2003, 5, 1951.
(n) Langer, P.; Ince, S. J.; Ley, S. V. J. Chem. Soc., Perkin
Trans. 1 1998, 3913. (o) Dimick, S. M.; Powell, S. C.;
McMahon, S. A.; Moothoo, D. N.; Naismith, J. H.; Toone,
E. J. J. Am. Chem. Soc. 1999, 121, 10286. (p) Corbell, J. B.;
Lundquist, J. J.; Toone, E. J. Tetrahedron: Assymmetry
2000, 11, 95. (q) Burke, S. T.; Zhao, Q.; Shuster, M. C.;
Kiessling, L. L. J. Am. Chem. Soc. 2000, 122, 4518.
(r) Grandjean, C.; Rommens, C.; Gras-Masse, H.; Melnyk,
O. Angew. Chem. Int. Ed. 2000, 39, 1068. (s)Hasegawa, T.;
Yonemura, T.; Matsuura, K.; Kobayashi, K. Tetrahedron
Lett. 2001, 42, 3989. (t) Fulton, D. A.; Stoddart, J. F.
Bioconjugate Chem. 2001, 12, 655. (u) Baussanne, I.;
Benito, J. M.; Mellet, C. O.; Fernandez, J. M. G.; Defaye, J.
ChemBioChem 2001, 2, 777. (v) Mellet, C. O.; Defaye, J.;
Fernandez, J. M. G. Chem.–Eur. J. 2002, 8, 1982.
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(10) (a) Perez-Balderas, F.; Santoyo-González, F. Synlett 2001,
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HRMS (MALDI-TOF): m/z calcd for C63H84O39Na, 1487.448;
found, 1487.622 (M + Na)+.
Acknowledgment
We thank Dirección General de Investigación Científica y Técnica
for financial support (BQ2002-03477).
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Synthesis 2005, No. 6, 939–944 © Thieme Stuttgart · New York