A new approach to a disaccharidic hapten containing a galactofuranosyl entity

Article abstract of DOI:10.1081/CAR-100108662

A short synthetic entry into the disaccharidic hapten β-D-Galf-(1→3)-α-D-Manp-O(CH₂)₈CO₂Me containing a galactofuranosyl entity at the non-reducing part is described. The synthetic scheme was designed in such a way that each required building block could be obtained by minimizing the number of chemical and purification steps. Indeed, compound 8 was obtained according to a four step-one pot preparation.

Full text of DOI:10.1081/CAR-100108662

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A NEW APPROACH TO A DISACCHARIDIC HAPTEN
CONTAINING A GALACTOFURANOSYL ENTITY
Vincent Ferrières a , Myriam Roussel a , Muriel Gelin a & Daniel Plusquellec a
a Ecole Nationale Supérieure de Chimie de Rennes, Synthèses et Activations de
Biomolécules, CNRS UMR 6052, Institut de Chimie de Rennes , Avenue du Général
Leclerc, Rennes, F-35700, France
Published online: 19 Aug 2006.
To cite this article: Vincent Ferrières , Myriam Roussel , Muriel Gelin & Daniel Plusquellec (2001) A NEW APPROACH TO A
DISACCHARIDIC HAPTEN CONTAINING A GALACTOFURANOSYL ENTITY , Journal of Carbohydrate Chemistry, 20:9, 855-865
To link to this article: http://dx.doi.org/10.1081/CAR-100108662
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J. CARBOHYDRATE CHEMISTRY, 20(9), 855–865 (2001)
A NEW APPROACH TO A DISACCHARIDIC
HAPTEN CONTAINING A
GALACTOFURANOSYL ENTITY1, 2
Vincent Ferrières,* Myriam Roussel, Muriel Gelin,
and Daniel Plusquellec
Ecole Nationale Supérieure de Chimie de Rennes,
Synthèses et Activations de Biomolécules, CNRS UMR 6052,
Institut de Chimie de Rennes, Avenue du Général Leclerc,
F-35700 Rennes, France
ABSTRACT
A short synthetic entry into the disaccharidic hapten ꢀ-D-Galf-(1→3)-ꢁ-D-
Manp-O(CH2)8CO2Me containing a galactofuranosyl entity at the non-reduc-
ing part is described. The synthetic scheme was designed in such a way that
each required building block could be obtained by minimizing the number of
chemical and purification steps. Indeed, compound 8 was obtained according
to a four step–one pot preparation.
INTRODUCTION
Worldwide each year, a large number of illnesses due to parasites are re-
ported. This can be explained by the natural outstanding diversity of parasites
which carry pathogenic agents and by their high potential of adaptability to the
contaminated host.3 Generally, host and parasite are able to live in harmony. Nev-
ertheless, Aspergillus, Leishmania and Trypanosoma species induce severe dis-
eases. For instance, T. gambiense and T. rhodesiense are responsible for sleeping
sickness in West and East Africa, respectively, while American or Chagas disease
originates from T. cruzi.3 Moreover, increasing human migrations result in exotic
*Corresponding author.
855
Copyright © 2002 by Marcel Dekker, Inc.
www.dekker.com

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FERRIÈRES ET AL.
Scheme 1. Retrosynthetic scheme for the preparation of disaccharide 1.
parasitoses from African and South American continents appearing more fre-
quently in the northern hemisphere. The clinical effects of these diseases may be
caused by a number of biomolecules such as proteins, glycoproteins and/or gly-
colipids. Among the latter, it was established that the epitopic unit of glycoconju-
gates, carried by infective microorganisms, contains galactofuranose (Galf)
residues as the non-reducing end.4
Considering our interest in hexofuranose chemistry,5 we present herein a
convenient access to the disaccharidic hapten 1 (Scheme 1) characterized by a ꢀ-
D-Galf entity and a functionalized spacer for further connection to a carrier. Our ap-
proach relies on (i) a specific synthesis of galactofuranosyl donors 2, (ii) a concise
ꢁ-D-mannosylation of the spacer arm via the persilylated mannopyranosyl iodide
4 and (iii) a highly regioselective furanosylation reaction of diol 3.
RESULTS AND DISCUSSION
The known octyl galactofuranoside 5 was obtained from D-Gal according to
a procedure developed in our laboratory6 and then benzoylated (Scheme 2). Sub-
sequent acetolysis under conditions worked out for the preparation of per-O-
acetyl-hexofuranoses7 was unfortunately unsuccessful, probably because of
greater electron withdrawing effects of benzoyl groups as compared to those of
acetyl units. Therefore, substituting acetic anhydride by the more reactive trifluo-
roacetic anhydride under carefully controlled acidic conditions afforded the
anomeric trifluoroacetyl furanose 7 without ring expansion. This intermediate

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857
Reagents and conditions: (a) BzCl, Py (98%); (b) (CF3CO)2O, H2SO4, CH2Cl2 (80%); (c)
RSH, BF3ꢄOEt2 (R ꢂ Ph, 91%; R ꢂ Et, 72%).
Scheme 2. Preparation of galactofuranosyl donors 2a and 2b.
could be isolated as a mixture of ꢁ,ꢀ -anomers (ꢁ/ꢀ ꢂ 1:4.6) but was best used for
further thioglycosidation just after simple work-up. Reaction of 7 with thiophenol
or ethanethiol, promoted by boron trifluoride-diethyl ether complex, resulted in the
specific formation of ꢀ-thioglycofuranosides 2a and 2b, respectively.
Parallel to this sequence, we also focused our attention on a short entry into
the mannopyranosidic acceptor 3. Amongst various hypotheses, we considered the
glycosyl iodide approach8 in order to shorten the time consuming preparation of 3.9
Indeed, persilylation of free D-mannose (D-Man) occurred in pyridine in 30 min us-
ing hexamethyldisilazane (HMDS) and chlorotrimethylsilane (TMSCl) as silylat-
ing agents (Scheme 3). The resulting anomeric mixture (ꢁ/ꢀ ꢂ 1:6.7), exclusively
in the pyranose form as revealed by NMR analysis, quantitatively reacted with
iodotrimethylsilane (TMSI) to give the key donor 4. Glycosylation of 8-ethoxy-
carbonyloctanol was then carried out in dichloromethane in the presence of steri-
cally hindered 2,6-di-tert-butyl-4-methylpyridine (DTBMP) used as acid scav-
enger. The glycosylation step was followed by simple in situ methanolysis of silyl
ethers. However, under these conditions, a first attempt to mannosylate the ꢃ-func-
tionalized alcohol yielded an anomeric mixture of mannopyranoside 8ꢁ,ꢀ. To
overcome this problem, acetylation of 8ꢁ,ꢀ followed by anomerization under the
action of ferric chloride10 and transesterification afforded the required pure 8ꢁ.
Nevertheless, in order to shorten this multi-step sequence, we expected that a di-
astereospecific mannosidation would occur using the well known in situ anomer-
ization approach.11 Therefore, after optimization, best results were obtained by: (i)
synthesizing the donor 4 from persilylated mannopyranose in 45 min, (ii) effecting
the anomerization catalyzed by tetrabutylammonium iodide (TBAI) in 15 min, and
Reagents and conditions: (a) HMDS, TMSCl, Py; (b) TMSI, CH2Cl2; (c) TBAI,
HO(CH2)8CO2Et, DTBMP; MeOH (55% from D-Man); (d) PhCH(OMe)2, ZnCl2,
AcOEt (44%).
Scheme 3. Synthesis of the mannopyranosidic building block 3.

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FERRIÈRES ET AL.
(iii) simultaneously adding 8-ethoxycarbonyloctanol and the base. After in situ
desilylation, this procedure gave the target ꢁ-mannopyranoside 8ꢁ in 55% overall
yield from D-Man, i.e., approximately 90% for each chemical step. Finally, selec-
tive 4,6-O-benzylidenation was achieved by transacetalation using benzaldehyde
dimethyl acetal and affording selectively acceptor 3.
Having the required building blocks in hand, we next investigated the cou-
pling reaction. Furanosylation of 8-ethoxycarbonyloctanol, yielding the protected
galactofuranoside 9, was first achieved under standard activation conditions, i.e.,
N-iodosuccinimide (NIS) and trimethylsilyl trifluoromethanesulfonate (TMSOTf),
of both phenyl and ethyl thiogalactofuranosides 2a and 2b, respectively (Scheme
4). A better glycosylation yield was obtained from ethyl derivative 2b (52% vs
40%), thus denoting a higher reactivity of 2b over 2a.12 In this context, glycosyla-
tion of diol acceptor 3 was performed using 2b as the furanosyl donor. Bis-glyco-
furanosylation of the mannosidic acceptor was avoided by carrying out the cou-
pling reaction at 0°C. Under these conditions, the desired ꢀ-(1→3)-disaccharide 10
was obtained with high regioselectivity (no trisaccharide was identified) and iso-
lated in 46 % yield.
Finally, deprotection of hydroxyl groups and transesterification of the ethyl
ester of compound 9 were simultaneously achieved under Zemplen conditions to
afford the desired galactofuranoside 11. Moreover, a similar debenzoylation pro-
cedure was followed by hydrogenolytic removal of the 4,6-benzylidene acetal cat-
alyzed over Pd/C that allowed the synthesis of the targeted hapten 1 in 90% yield
for the last two steps.
Compounds 9, 10, 11 and 1 were easily characterized on the grounds of sig-
nals identified by COSY and heteronuclear 1H-13C 2D experiments. The ꢀ config-
Reagents and conditions: (a) HO(CH2)2CO2Et, NIS, TMSOTf, 4Å MS, CH2Cl2 (40%
from 2a, 62% from 2b); (b) 3, NIS, TMSOTf, 4Å MS, CH2Cl2 (46%); (c) NaOMe,
MeOH (93%); (d) NaOMe, MeOH; H2 Pd/C (90%).
Scheme 4. Synthesis of the targeted haptens 11 and 1.

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859
uration of the furanosyl entities was based on a small coupling constant between
H-1ꢅ and H-2ꢅ (J1ꢅ,2ꢅ ꢀ0 Hz). Moreover, glycosylation of the equatorial hydroxyl
of 3 was evidenced, for disaccharide 10, by a typical downfield chemical shift for
C-3 (ꢆC-3 ꢂ 72.6 ppm for 3 vs. ꢆ C-3 ꢂ 76.8 ppm for 10) as well as upfield shift for
both adjacent carbon atoms C-2 (ꢆC-2 ꢂ 72.2 ppm for 3 vs. ꢆ C-2 ꢂ 68.7 ppm for
10) and C-4 (ꢆC-4 ꢂ 68.5 ppm for 3 vs. ꢆ C-4 ꢂ 72.0 ppm for 10).(13) A similar be-
haviour was observed by comparison of C-3, C-2 and C-4 chemical shifts from
compounds 8 and 1, respectively.
In summary, we have developed an efficient route toward the synthesis of a
glycosidic hapten characterized by the disaccharide ꢀ-D-Galf-(1→3)-ꢁ-D-Manp
which mimics the non-reducing and epitopic part of the main lipopeptidophospho-
glycan (LPPG) found in T. cruzi. Particular attention has been given to establish-
ing (i) the specific formation of the furanoid ring and (ii) a short synthesis of the
mannopyranosyl moiety. The key step of our strategy consisted in a four step (ac-
tivation, anomerization, diastereospecific glycosidation without anchimeric assis-
tance of participating groups, and deprotection)–one pot preparation of mannoside
8 and resulted in an important decrease in the number of purification and isolation
steps required and in a significantly increased overall yield. Continuing efforts are
currently under way for the chemical synthesis of natural derivatives containing
hexofuranosyl residues.
EXPERIMENTAL
General Methods. While all chemicals were commercially available and
used as received, octyl D-galactofuranoside (5) was prepared according to ref. 6.
All reactions were performed under a nitrogen atmosphere. TLC analyses were
carried out on precoated non-activated plates (E. Merck 60 F254) with detection by
UV absorption (254 nm), when applicable, and charring with 5% sulfuric acid in
ethanol. For column chromatography, E. Merck 60H (5–40 ꢇm) silica gel was
used. Optical rotations were determined with a Perkin-Elmer 341 polarimeter at
20 °C using a 1 dm cell. Melting points were determined using a Reichert micro-
1
scope with heating plate and are uncorrected. H and 13C NMR spectra were
recorded on a Bruker ARX 400 spectrometer at 400 and 100 MHz, respectively.
Chemical shifts are given in ppm (ꢆ). CDCl3 or CD3OD and trimethylsilane were
used as solvent and internal standard, respectively. Microanalyses were performed
by the Service de Microanalyses de l’ICSN (Gif sur Yvette, France).
n-Octyl 2,3,5,6-Tetra-O-benzoyl-D-galactofuranoside (6). To a solution
of 56 (1.53 g, 5.20 mmol,ꢀ/ꢁꢂ1.86:1) in dry pyridine (17 mL) cooled at 0°C was
added benzoyl chloride (2.92 mL, 25.15 mmol). After stirring for 3 h and concen-
tration under reduced pressure, the resulting crude mixture was diluted with
dichloromethane. The organic layer was successively washed with 5% aqueous
HCl, saturated aqueous K2CO3 and water, dried (MgSO4), and concentrated.
Flash-chromatography (9:1 light petroleum/ethyl acetate) then afforded 6 (2.70

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FERRIÈRES ET AL.
g,ꢀ/ꢁꢂ1.9:1) in 73% yield as an amorphous solid. TLC (4:1 light petroleum/ethyl
acetate) Rf 0.6. 6ꢀ: 1H NMR (CDCl3) ꢆ 8.08ꢈ7.86 (m, 8 H, C6H5); 7.58ꢈ7.18 (m,
12 H, C6H5); 6.10ꢈ6.05 (m, 1 H, H-5); 5.62 (d, 1 H, H-3, J3,4ꢂ5.1 Hz); 5.46 (s, 1
H, H-1); 5.30 (s, 1 H, H-2); 4.78 (dd, 1 H, H-6a, J6a,6bꢂ11.7 Hz, J6a,5ꢂ4.6 Hz);
4.73 (dd, 1 H, H-6b, J6b,5ꢂ6.6 Hz); 4.63 (dd, 1 H, H-4, J4,5ꢂ3.6 Hz); 3.73 (dt, 1 H,
2
3
3
OCH2CH2, Jꢂ9.2 Hz, Jꢂ7.1 Hz); 3.53 (dt, 1 H, OCH2CH2, Jꢂ6.1 Hz);
1.67ꢈ1.54 (m, 2 H, OCH2CH2); 1.40ꢈ1.15 [m, 10 H, (CH2)5]; 0.86 (t, 3 H, CH3,
3Jꢂ6.6 Hz). 13C NMR (CDCl3) ꢆ 166.1, 165.7, 165.5 (CO); 133.4, 133.3, 133.2,
133.1 (Cipso); 130.0ꢈ128.3 (C6H5); 105.6 (C-1); 82.1 (C-2); 81.2 (C-4); 77.6 (C-
3); 70.3 (C-5); 67.6 (OCH2CH2); 63.5 (C-6); 31.8, 29.5, 29.4, 29.3, 26.2, 22.7
[(CH2)6]; 14.1 (CH3). 6ꢁ: 13C NMR (CDCl3) ꢆ 166.0, 165.9, 165.7, 165.5 (CO);
133.4ꢈ128.2 (C6H5); 100.5 (C-1); 78.5, 77.8 (C-2, C-4); 74.9 (C-3); 71.9, 69.1 (C-
5, OCH2CH2); 63.0 (C-6); 31.8, 29.3, 29.2, 29.1, 25.9, 22.6 [(CH2)6]; 14.0 (CH3).
Anal. Calcd for C42H46O10 (710.83): C, 70.97; H, 6.52. Found: C, 70.65; H,
6.50.
2,3,5,6-Tetra-O-benzoyl-1-O-trifluoroacetyl-D-galactofuranose (7). To
a solution of 6 (1.585 g, 2.24 mmol) in dry dichloromethane (24 mL) were added,
at 0°C, trifluoroacetic anhydride (1.27 mL, 8.95 mmol) and sulfuric acid (358 ꢇL,
6.72 mmol). After stirring for 35 min, neutralization with triethylamine and con-
centration under reduced pressure, the residue was subjected to column chro-
matography (5:5:0.01 light petroleum/ethyl acetate/triethylamine) that afforded an
anomeric mixture of 7 (1.24 g, 80%,ꢀ/ꢁꢂ4.6:1) as an amorphous compound. This
product could be characterized by NMR analysis and thus used for subsequent re-
action without further purification. TLC (5:5:0.01 light petroleum/ethyl acetate/tri-
ethylamine) Rf 0.4. 7ꢀ: 1H NMR (CDCl3) ꢆ 8.10ꢈ7.26 (m, 20 H, C6H5); 6.07 (dt,
1 H, H-5, J4,5ꢂ4.0 Hz, 3Jꢂ6.6 Hz); 5.71 (s, 1 H, H-1); 5.64 (d, 1 H, H-3, J3,4ꢂ5.1
Hz); 5.51 (s, 1 H, H-2); 4.86 (dd, 1 H, H-4); 4.78 (dd, 1 H, H-6a, J5,6aꢂ4.6 Hz,
J
6a,6bꢂ12.0 Hz); 4.71 (dd, 1 H, H-6b, J5,6bꢂ7.1 Hz). 13C NMR (CDCl3) ꢆ 166.2,
165.8, 165.7, 165.6 (CO); 133.7ꢈ128.3 (C6H5); 100.9 (C-1); 82.7, 81.6 (C-4,
C-2); 77.7 (C-3); 70.5 (C-5); 63.6 (C-6). 19F NMR (CDCl3) ꢆ ꢈ75.5 (CF3). 7ꢁ: 1H
NMR (CDCl3) ꢆ 8.10ꢈ7.26 (m, 20 H, C6H5); 6.12 (t, 1 H, H-2, J1,2ꢂJ2,3ꢂ4.6 Hz);
3
5.97 (1 H, H-5, J4,5ꢂ6.4 Hz, Jꢂ3.6 Hz); 5.84 (d, 1 H, H-1); 5.54 (t, 1 H, H-3,
J3,4ꢂ4.6 Hz); 4.84 (dd, 1 H, H-6a, J6a,6bꢂ12.2 Hz); 4.72 (dd, 1 H, H-6b); 4.56 (dd,
1 H, H-4). 13C NMR (CDCl3) ꢆ 166.3, 166.0, 165.7, 165.5 (CO); 95.9 (C-1); 79.2,
77.6 (C-4, C-2); 75.7 (C-3); 72.2 (C-5); 63.1 (C-6). 19F NMR (CDCl3) ꢆ ꢈ75.5
(CF3).
Phenyl 2,3,5,6-Tetra-O-benzoyl-1-thio-ꢀ-D-galactofuranoside (2a). To
a solution of 7 (1.80 g, 2.60 mmol) in dry dichloromethane (18 mL) were succes-
sively added, at 0°C, thiophenol (0.40 mL, 3.9 mmol) and BF3.OEt2 (0.66 mL,
5.2 mmol). The reaction was then monitored by TLC (3:2 light petroleum/ethyl
acetate). After complete consumption of 7, the mixture was diluted with
dichloromethane (75 mL), washed with 5% aqueous NaHCO3 and with water. The
organic layer was finally dried (MgSO4), concentrated, and the residue was chro-

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861
matographically (4:1 light petroleum/ethyl acetate) purified. This procedure gave
2.00 g (89%) of desired 2a. TLC (3:2 light petroleum/ethyl acetate) Rf 0.7. mp
ꢂ98–100 °C (ethyl acetate/light petroleum). [ꢁ]2D0ꢈ66 (c 1.0, CH2Cl2). 1H NMR
(CDCl3) ꢆ 8.06ꢈ7.21 (m, 25 H, C6H5); 6.11 (dt, 1 H, H-5, J5,6bꢂ6.9 Hz,
J5,6aꢂJ5,4ꢂ4.6 Hz); 5.84 (s, 1 H, H-1); 5.71 (d, 1 H, H-3, J3,4ꢂ5.0 Hz); 5.67 (s, 1
H, H-2); 4.95 (t, 1 H, H-4); 4.76 (dd, 1 H, H-6a, J6a,6bꢂ11.8 Hz); 4.71 (dd, 1 H, H-
6b). 13C NMR (CDCl3) ꢆ 166.0, 165.7, 165.5, 165.3 (CO); 133.6, 133.5, 133.3,
133.1 (COCipso); 132.4 (SCipso); 130.0ꢈ127.3 (C6H5); 91.3 (C-1); 82.4 (C-2); 81.5
(C-4); 77.8 (C-3); 70.3 (C-5); 63.4 (C-6).
Anal. Calcd for C40H32O9S (688.76): C, 69.76; H, 4.68. Found C, 69.83; H,
4.69.
Ethyl 2,3,5,6-Tetra-O-benzoyl-1-thio-ꢀ-D-galactofuranoside (2b).
Product 2b was prepared according to the previous procedure starting with 7 (1.80
g, 2.60 mmol), ethanethiol (0.45 mL, 5.9 mmol) and BF3.OEt2 (0.66 mL, 5.2
mmol). Work-up and chromatographic (4:1 light petroleum/ethyl acetate) purifi-
cation afforded 2b (1.20 g) in 72% yield. TLC (7:3 light petroleum/ethyl acetate)
Rf 0.7. [ꢁ]2D0ꢈ26 (c 1.0, CH2Cl2). 1H NMR (CDCl3) ꢆ 8.10ꢈ7.26 (m, 20 H, C6H5);
6.13ꢈ6.09 (m, 1 H, H-5); 5.67 (d, 1 H, H-1, J1,2ꢂ1.0 Hz); 5.67ꢈ5.66 (m, 1 H,
H-3); 5.50 (t, 1 H, H-2, J2,3ꢂ1.0 Hz); 4.84 (t, 1 H, H-4, J3,4ꢂJ4,5ꢂ4.0 Hz); 4.77
(dd, 1 H, H-6a, J6a,6bꢂ11.7 Hz, J6a,5ꢂ4.6 Hz); 4.74 (dd, 1 H, H-6b, J6b,5ꢂ6.6 Hz);
2.78 (dq, 1 H, CH2CH3, 2Jꢂ12.7 Hz, 3Jꢂ7.6 Hz); 2.69 (dq, 1 H, CH2CH3, 3Jꢂ7.6
Hz); 1.33 (t, 3 H, CH2CH3). 13C NMR (CDCl3) ꢆ 166.1, 165.7, 165.5, 165.4 (CO);
133.4, 133.3, 133.2, 133.1 (Cipso); 130.1, 130.0, 129.9, 129.7, 128.5, 128.4, 128.3
(C6H5); 88.2 (C-1); 82.9 (C-2); 81.1 (C-4); 77.9 (C-3); 70.2 (C-5); 63.5 (C-6); 25.3
(CH2CH3); 14.9 (CH2CH3).
Anal Calcd for C36H32O9S (640.71): C, 67.49; H 5.03. Found C, 67.49; H,
5.19.
8-Ethoxycarbonyloctyl ꢁ-D-Mannopyranoside (8). To a solution of D-
mannose (5.00 g, 27.8 mmol) in dry pyridine (80 mL) were successively added
hexamethyldisilazane (32.2 mL, 152.8 mmol) and chlorotrimethylsilane (19.4 mL,
152.8 mmol). After stirring at room temperature for 35 min, the solvent was re-
moved under reduced pressure. The resulting mixture was then diluted with Et2O
(100 mL) and washed with 5 % aqueous HCl, saturated aqueous NaHCO3 and wa-
ter. The organic layer was finally dried (MgSO4) and concentrated to give an
anomeric mixture of trimethylsilyl 2,3,4,6-tetra-O-trimethylsilyl-D-mannopyra-
noside (6) (14.87 g,ꢁ/ꢀꢂ6.7:1). TLC (9:1 light petroleum/diethylether) Rf 0.8. Se-
lected 1H NMR data14 for 6: (CDCl3) ꢆ 4.90 (s, 0.87 H, H-1ꢁ); 4.64 (s, 0.13 H, H-
1ꢀ). Selected 13C NMR data14 for 6: (CDCl3) ꢆ 95.6 (C-1ꢁ); 95.5 (C-1ꢀ).
The crude oil (3.93 g, 7.26 mmol) was diluted in dry dichloromethane (20
mL) before adding freshly distilled iodotrimethylsilane (1.1 mL, 7.99 mmol). The
mixture was stirred at room temperature for 45 min, tetrabutylammonium iodide
(2.68 g, 7.26 mmol) was added and stirred for 15 min more before adding a
dichloromethane (20 mL) solution of 8-ethoxycarbonyloctan-1-ol (2.93 g, 14.5

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mmol) and 1.49 g (7.26 mmol) of 2,6-di-tert-butyl-4-methylpyridine. The reaction
mixture was stirred at room temperature for 6 h, and final desilylation was per-
formed in 30 min with methanol (60 mL). The resulting solution was made neutral
(triethylamine), concentrated, and purification by column chromatography (9:1
dichloromethane/methanol) afforded the target compound 8 (1.45g) in 55% global
yield. TLC (8:1 dichloromethane/methanol) Rf 0.3. [ꢁ]2D0 ꢉ28 (c 1.0, methanol)
[lit.15 [ꢁ]2D5ꢉ48 (c 0.75, water)]. 1H NMR (CDCl3) ꢆ 4.70 (s, 1 H, H-1); 4.10ꢈ4.05
(m, 2 H, CO2CH2CH3); 3.79ꢈ3.72 (m, 2 H, H-2, H-6a); 3.70ꢈ3.62 (m, 3 H, H-3,
H-6b, OCH2CH2); 3.58 (t, 1 H, H-4, J3,4ꢂJ4,5ꢂ9.5 Hz); 3.50ꢈ3.43 (m, 1 H, H-5);
3
3.40ꢈ3.35 (m, 1 H, OCH2CH2); 2.27 (t, 2 H, CH2CH2CO2Et, Jꢂ7.4 Hz);
1.62ꢈ1.50 [m, 4 H, (CH2)2]; 1.38ꢈ1.24 [m, 8 H, (CH2)4]; 1.21 (t, 3 H,
3
CO2CH2CH3, Jꢂ7.1 Hz). 13C NMR (CD3OD) ꢆ 175.5 (CO); 101.4 (C-1); 74.4
(C-5); 72.6 (C-3); 72.2 (C-2); 68.5 (C-4, OCH2CH2); 62.8 (C-6); 61.3
(CO2CH2CH3); 35.0 (CH2CH2CO2Et); 30.5, 30.3, 30.2, 30.0, 27.2, 26.0 [(CH2)6];
14.6 (CO2CH2CH3).
8-Ethoxycarbonyloctyl 4,6-O-Benzylidene-ꢁ-D-mannopyranoside (3).
To a solution of 8 (0.90 g, 2.47 mmol) in ethyl acetate (5 mL) were successively
added ZnCl2 (0.36 g, 2.64 mmol) and benzaldehyde dimethyl acetal (408 ꢇL, 2.64
mmol). After stirring at 50 °C for 1.5 h, the reaction mixture was cooled and then
washed with 10% aqueous Na2S2O4, saturated aqueous NaHCO3 and water. The
organic layer was dried (MgSO4) and concentrated under reduced pressure. The
target compound 3 was finally purified by column chromatography (3:2 light
petroleum/ethyl acetate) and isolated in 44% yield (488 mg) as a colorless oil. TLC
(1:1 light petroleum/ethyl acetate) Rf 0.4. [ꢁ]2D0 ꢉ37 (c 1.2, CHCl3) [lit.9 [ꢁ]2D0
ꢉ37 (c 1.2, CHCl3)]. 1H NMR (CDCl3) ꢆ 7.51ꢈ7.48 (m, 2 H, C6H5); 7.39ꢈ7.35
(m, 3 H, C6H5); 5.56 (s, 1 H, PhCH); 4.82 (s, 1 H, H-1); 4.29ꢈ4.23 (m, 1 H, H-6a);
4.14ꢈ4.09 (m, 2 H, CO2CH2CH3); 4.10ꢈ4.04 (m, 1 H, H-3); 4.01ꢈ3.98 (m, 1 H,
H-2); 3.91 (t, 1 H, H-4, J3,4ꢂJ4,5ꢂ9.1 Hz); 3.83ꢈ3.79 (m, 2 H, H-6b, H-5); 3.68
(dt, 1 H, OCH2CH2, 2Jꢂ9.6 Hz, 3Jꢂ6.6 Hz); 3.40 (dt, 1 H, OCH2CH2, 3Jꢂ6.6 Hz);
2.29 (t, 2 H, CH2CH2CO2Et, 3Jꢂ7.6 Hz); 1.64ꢈ1.56 [m, 4 H, (CH2)2]; 1.38ꢈ1.29
3
[m, 8 H, (CH2)4]; 1.25 (t, 3 H, CO2CH2CH3, Jꢂ7.1 Hz). 13C NMR (CDCl3) ꢆ
174.0 (CO); 137.2 (Cipso); 129.2, 128.3, 126.2 (C6H5); 102.2 (PhCH); 100.1 (C-1);
77.0 (C-4); 71.1 (C-3); 68.8 (C-6); 68.6 (C-3); 68.0 (OCH2CH2); 63.0 (C-5); 60.2
(CO2CH2CH3); 34.3 (CH2CH2CO2Et); 29.3, 29.1, 29.0, 26.0, 24.9 [(CH2)6]; 14.2
(CO2CH2CH3).
8-Ethoxycarbonyloctyl 2,3,5,6-Tetra-O-benzoyl-ꢀ-D-galactofuranoside
(9). To a solution of donor 2b (0.093 g, 0.145 mmol) and 8-ethoxycarbonyloc-
tanol (0.024 g, 0.212 mmol) in dry dichloromethane (1 mL) in the presence of
molecular sieves (4 Å, 0.20 g), cooled at 0°C and protected from light, were suc-
cessively added N-iodosuccinimide (26 mg, 0.145 mmol) and trimethylsilyl triflate
(2 ꢇL, 0.012 mmol). After stirring for 3 h at 0°C and 4 h at room temperature, the
reaction mixture was made neutral by a few drops of triethylamine, filtered over a
bed of celite, concentrated and finally purified by column chromatography (7:2:1

ORDER
REPRINTS
DISACCHARIDIC HAPTEN
863
light petroleum/ethyl acetate/dichloromethane). Product 9 (0.059 g) was thus iso-
lated in 52% yield. TLC (7:2:1 light petroleum/ethyl acetate/dichloromethane) Rf
0.4. 1H NMR (CDCl3) ꢆ 8.09ꢈ7.89 (m, 8 H, C6H5); 7.59ꢈ7.26 (m, 12 H, C6H5);
6.10ꢈ6.06 (m, 1 H, H-5); 5.63 (d, 1 H, H-3, J3,4ꢂ5.1 Hz); 5.47 (s, 1 H, H-1); 5.30
(s, 1 H, H-2); 4.79 (dd, 1 H, H-6a, J6a,6bꢂ11.7 Hz, J6a,5ꢂ4.6 Hz); 4.74 (dd, 1 H, H-
6b, J6b,5ꢂ7.1 Hz); 4.64 (dd, 1 H, H-4, J4,5ꢂ3.6 Hz); 4.15ꢈ4.09 (m, 2 H,
2
3
CO2CH2CH3); 3.75 (dt, 1 H, OCH2CH2, Jꢂ9.6 Hz, Jꢂ6.6 Hz); 3.53 (dt, 1 H,
OCH2CH2, 3Jꢂ6.1 Hz); 2.26 (t, 2 H, CH2CH2CO2Et, 3Jꢂ7.4 Hz); 1.67ꢈ1.56 [m,
4 H, (CH2)2]; 1.41ꢈ1.21 [m, 8 H, (CH2)4]; 1.25 (t, 3 H, CO2CH2CH3, 3Jꢂ7,1 Hz).
13C NMR (CDCl3) ꢆ 173.8 (COOEt); 166.1, 165.7, 165.6, 165.4 (OCOPh); 133.5,
133.3, 133.2, 133.1 (Cipso); 129.9ꢈ128.3 (C6H5); 105.5 (C-1); 82.0 (C-2); 81.2 (C-
4); 77.6 (C-3); 70.3 (C-5); 67.6 (OCH2CH2); 63.5 (C-6); 60.1 (CO2CH2CH3); 34.3
(CH2CH2CO2Et); 29.4, 29.3, 29.2, 29.1, 26.1, 24.9 [(CH2)6]; 14.2 (CO2CH2CH3).
Anal Calcd for C45H48O12 (780.87): C, 69.22; H, 6.20. Found C, 69.15; H,
6.25.
8-Ethoxycarbonyloctyl 2,3,5,6-Tetra-O-benzoyl-ꢀ-D-galactofuranosyl-
(1(3)-4,6-O-benzylidene-ꢁ-D-mannopyranoside (10). Galactofuranosyl donor
2b (0.17 g, 0.27 mmol) and glycosyl acceptor 3 (0.10 g, 0.22 mmol) were dissolved
in anhydrous dichloromethane (4 mL) containing molecular sieves (4 Å, 0.20 g).
The reaction mixture was then protected from light and cooled to 0°C before
adding N-iodosuccinimide (60 mg, 0.27 mmol) and trimethylsilyl triflate (9 ꢇL,
0.04 mmol) and stirring for 15 min. After completion of the reaction, the media was
quenched with several drops of triethylamine until it turned into a yellow solution.
The resulting mixture was filtered over a bed of celite, concentrated under reduced
pressure and finally subjected to column chromatography (4:1 toluene/ethyl ac-
etate). This procedure provided the required disaccharide 10 (0.103 g) in 46%
yield. TLC (4:1 toluene/ethyl acetate) Rf 0.3. [ꢁ]2D0ꢉ61 (c 1.0, CHCl3). 1H NMR
(CDCl3) ꢆ 8.04ꢈ7.81 (m, 8 H, C6H5); 7.59ꢈ7.16 (m, 17 H, C6H5); 5.90 (ddd, 1 H,
H-5ꢅ, J5ꢅ,6ꢅaꢂ8.6 Hz,, J5ꢅ,6ꢅbꢂ5.6 Hz, J5ꢅ,4ꢅꢂ3.0 Hz); 5.56 (dd, 1 H, H-3ꢅ, J3ꢅ,4ꢅꢂ5.6
Hz, J3ꢅ,2ꢅꢂ1.5 Hz); 5.49 (s, 1 H, H-1ꢅ); 5.46 (s, 1 H, PhCH); 5.44 (d, 1 H, H-2ꢅ);
4.93 (s, 1 H, H-1); 4.74 (dd, 1 H, H-4ꢅ); 4.59 (dd, 1 H, H-6ꢅa, J6ꢅa,6ꢅbꢂ12.2 Hz,);
4.31ꢈ4.26 (m, 2 H, H-4, H-5); 4.16ꢈ4.02 (m, 5 H, H-2, H-3, H-6ꢅb,
CO2CH2CH3); 3.92 (dd, 1 H, H-6a, J6a,6bꢂ10.2 Hz, J6a,5ꢂ4.6 Hz); 3.90 (dd, 1H,
H-6b, J6b,5ꢂ5.1 Hz); 3.71 (dt, 1 H, OCH2CH2, 2Jꢂ9.6 Hz, 3Jꢂ6.6 Hz); 3.41 (dt, 1
H, OCH2CH2, 3Jꢂ6.6 Hz); 2.28 (t, 2 H, CH2CH2CO2Et, 3Jꢂ7.1 Hz); 1.62ꢈ1.58
[m, 4 H, (CH2)2]; 1.36ꢈ1.21 [m, 8 H, (CH2)4]; 1.23 (t, 3 H, CO2CH2CH3, 3Jꢂ7.1
Hz). 13C NMR (CDCl3) ꢆ 166.0, 165.9, 165.7, 165.5 (CO); 137.3 (CHCipso); 135.5,
133.5, 133.1, 132.3 (COCipso); 130.0ꢈ125.9 (C6H5); 102.4 (C-1ꢅ); 102.0 (PhCH);
100.1 (C-1); 82.4 (C-2ꢅ); 81.3 (C-4ꢅ); 77.2 (C-3ꢅ); 76.8 (C-3); 72.0 (C-4); 70.1 (C-
5ꢅ); 68.9 (C-5); 68.7 (C-2); 68.1 (OCH2CH2); 64.2 (C-6ꢅ); 63.6 (C-6); 60.1
(CO2CH2CH3); 34.3 (CH2CH2CO2Et); 30.3, 29.7, 29.2, 29.1, 26.0, 24.9 [(CH2)6];
14.2 (CO2CH2CH3).
Anal. Calcd for C58H62O16 (1015.13): C, 68.62; H, 6.16. Found C, 68.45; H,
6.20.

ORDER
REPRINTS
864
FERRIÈRES ET AL.
8-Methoxycarbonyloctyl ꢀ-D-Galactofuranoside (11). To a solution of 9
(0.050 g, 64 ꢇmol) in anhydrous methanol (2 mL) was added sodium (0.1 mg). Af-
ter stirring at room temperature for 24 h, the reaction was made neutral with IR120-
Hꢉ-form resin, filtered and concentrated under reduced pressure. After removal of
the solvent, the desired product 11 was purified by flash-chromatography (9:1
dichloromethane/methanol) and isolated (0.021 g) in 93% yield. TLC (9:1
dichloromethane/methanol) Rf 0.3. [ꢁ]2D0ꢈ66 (c 1.0, MeOH) [lit9 [ꢁ]2D0ꢈ73 (c 0.6,
EtOH)]. 1H NMR (CD3OD) ꢆ 4.75 (d, 1 H, H-1, J1,2ꢂ1.8 Hz); 3.90 (dd, 1 H, H-3,
J2,3ꢂ4.0 Hz, J3,4ꢂ6.6 Hz); 3.83 (dd, 1 H, H-2); 3.81 (dd, 1 H, H-4, J4,5ꢂ3.0 Hz);
3.65ꢈ3.50 (m, 7 H, H-5, H-6, H-6ꢅ, H-ꢁ, CH3); 3.37ꢈ3.28 (m, 1 H, H-ꢁꢅ); 2.22
3
(t, 2 H, CH2CO, Jꢂ7.5 Hz); 1.52ꢈ1.47 (m, 2 H, CH2ꢀ); 1.25ꢈ1.21 [m, 8 H,
(CH2)4]. 13C NMR (CD3OD) ꢆ 176.0 (CO); 109.4 (C-1); 84.0 (C-4); 83.4 (C-2);
78.7 (C-3); 72.4 (C-5); 68.9 (CH2ꢁ); 64.6 (C-6); 52.0 (CH3); 34.8 (CH2ꢀ); 30.7,
30.3, 30.1, 27.2, 26.0 [(CH2)6)].
8-Methoxycarbonyloctyl ꢀ-D-Galactofuranosyl-(1→3)-ꢁ-D-mannopyra-
noside (1). To a solution of disaccharide 10 (0.10 g, 0.097 mmol) in anhydrous
methanol (2 mL) was added a 0.1 M methanolic solution of sodium methoxide
(0.97 mL). After stirring at room temperature for 16 h, the reaction mixture was
made neutral with IR120-Hꢉ-form resin, filtered and concentrated under reduced
pressure: TLC (9:1 dichloromethane/methanol) Rf 0.4. The resulting crude prod-
uct was then subjected to hydrogenolysis in absolute ethanol (2 mL) using 10%
palladium activated on charcoal as catalyst. No transesterification was observed
under these conditions. After 48 h at room temperature, the catalyst was removed
by filtration, and the solvent was evaporated. A chromatographic purification (4:1
dichloromethane/methanol) provided 1 (45 mg, 90% over two steps): TLC (4:1
1
CH2Cl2/MeOH) Rf 0.4. [ꢁ]2D0 ꢉ61 (c 1.0, CHCl3). H NMR (CD3OD) ꢆ 4.99 (s,
1 H, H-1ꢅ); 4.69 (d, 1 H, H-1, J1,2ꢂ1.5 Hz); 4.02ꢈ3.98 (m, 1 H, H-3ꢅ); 3.97ꢈ3.94
(m, 2 H, H-2ꢅ, H-4ꢅ); 3.89ꢈ3.87 (m, 1 H, H-2); 3.79ꢈ3.73 (m, 2 H, H-3, H-6a);
3.67ꢈ3.46 (m, 7 H, H-5ꢅ, H-6ꢅa, H-4, H-5, OCH2CH2); 3.57 (s, 3 H, CO2CH3);
3.35 (dt, 1 H, OCH2CH2, 2Jꢂ9.6 Hz, 3Jꢂ6.6 Hz); 2.24 (t, 2 H, CH2CH2CO2Me,
3Jꢂ7.1 Hz); 1.57ꢈ1.49 [m, 4 H, (CH2)2]; 1.34ꢈ1.22 [m, 8 H, (CH2)4]. 13C NMR
(CD3OD) ꢆ 176.1 (CO); 106.5 (C-1ꢅ); 101.4 (C-1); 85.4 (C-4ꢅ); 82.8 (C-2ꢅ); 79.0
(C-3ꢅ); 77.5 (C-3); 74.5 (C-5); 72.5 (C-5ꢅ); 68.8 (C-2); 68.7 (OCH2CH2); 66.8
(C-4); 64.4 (C-6ꢅ); 62.9 (C-6); 52.0 (CO2CH3); 34.8 (CH2CH2CO2Me); 30.6, 30.4,
30.3, 30.1, 27.3, 26.0 [(CH2)6]. [ꢁ]2D0 (of peracetylated disaccharide) ꢉ12 (c 1.0,
CHCl3) [lit.9 [ꢁ]2D0ꢉ37 (c 1.2, CHCl3)].
ACKNOWLEDGMENTS
The authors are grateful to Thierry Benvegnu for helpful discussion, to Mar-
tine Lefeuvre for assistance in NMR analysis and to Jula Meyer (Erasmus fellow-
ship student) for her contribution to this project.

ORDER
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DISACCHARIDIC HAPTEN
865
REFERENCES
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Received June 5, 2001
Accepted November 7, 2001

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