Synthesis of a tri- and a tetradeoxy analogue of methyl 3,6-di-O-α-D-mannopyranosyl-α-D-mannopyranoside for investigation of the binding site of various plant lectins

Article abstract of DOI:10.1016/S0008-6215(98)00107-4

The synthesis of the 2,4,3'-trideoxy and 2,4,3',4'-tetradeoxy analogues of the trimannoside part of the core structure of N-linked glycoproteins, methyl 3,6-di-O-α-D-mannopyranosyl-α-D-mannopyranoside, is described. A 2,4-dideoxy (1→6)-linked disaccharide

Full text of DOI:10.1016/S0008-6215(98)00107-4

Carbohydrate Research 309 (1998) 207±212
Note
Synthesis of a tri- and a tetradeoxy analogue of
methyl 3,6-di-O-ꢀ-d-mannopyranosyl-ꢀ-d-
mannopyranoside for investigation of the
binding site of various plant lectins
Stefan Oscarson*, Par Svahnberg
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
S-106 91 Stockholm, Sweden
Received 6 January 1998; accepted 21 March 1998
Abstract
The synthesis of the 2,4,30-trideoxy and 2,4,30,40-tetradeoxy analogues of the trimannoside part
of the core structure of N-linked glycoproteins, methyl 3,6-di-O-ꢀ-d-mannopyranosyl-ꢀ-d-man-
nopyranoside, is described. A 2,4-dideoxy (1!6)-linked disaccharide was used as a common
intermediate acceptor, which was coupled with a 3-deoxy and a 3,4-dideoxy benzochlorosugar
donor, the latter prepared from methyl ꢀ-d-mannopyranoside in ®ve steps. Despite the acid-sen-
sitive donors and acceptor, acceptable glycosylation yields were obtained of both the trideoxy- and
the tetradeoxy trisaccharide using silver tri¯ate as a promoter (65 and 51%, respectively). Depro-
tection in one step then gave the target products. # 1998 Elsevier Science Ltd. All rights reserved
Keywords: Deoxysugars; Oligosaccharide synthesis; N-Linked glycoproteins; Concanavalin A
The branched core trisaccharide of N-linked gly-
coproteins, 3,6-di-O-ꢀ-d-mannopyranosyl-d-man-
nopyranose, binds selectively to a number of
legume lectins, i.e., the well-known jack bean lectin
Concanavalin A (Con A) [1]. To investigate these
bindings on a molecular level all the possible
monodeoxy derivatives of the methyl ꢀ-glycoside
of the core trisaccharide were synthesised [2].
Results from binding studies of these with Con A
showed that apart from the 3, 4 and 6-hydroxyl
groups of the 6-substituted mannose, which binds
to the lectin in the ``monosaccharide binding site'',
additional binding was found to the 2- and 4-
hydroxyl groups of the central mannose unit and
the 3- and 4-hydroxyl groups of the 3-substituted
mannose. Synthesis and binding studies of the 2,30-
and the 4,30-dideoxy derivatives corroborated these
®ndings [2±4]. To even further look into this bind-
ing the 2,4,30-trideoxy and the 2,4,30,40-tetradeoxy
analogues would be an asset. The synthesis of these
derivatives is described in this article and iso-
thermal titration microcalorimetry (ITC) measure-
ments of their binding to ConA has been
performed to give a very detailed picture of this
carbohydrate-protein interaction [4]. The thermo-
dynamic solution data also agrees well with the
* Corresponding author. Fax: +46 8-154-908
0008-6215/98/$Ðsee front matter # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00107-4

208
S. Oscarson, P. Svahnberg/Carbohydrate Research 309 (1998) 207±212
recent X-ray crystal structure of ConA complexed
with the trimannoside [5].
phine-triiodoimidazole [8] and thiocarbonyldiimi-
dazole [9]. Hence, new pathways were envisaged
exploiting the glycosylation of a common 2,4-
dideoxy disaccharide acceptor intermediate (8).
The known 4-OH disaccharide 6 [2] was treated
with triphenylphosphine and triiodoimidazole to
give the inverted 4-iodo compound 7 (90%)
(Scheme 2). Hydrogenolysis then gave the key
intermediate, the 2,4-dideoxy acceptor disaccharide
8 (42%) with a free 3-OH group. The rather low
yield in the hydrogenation is explained by the con-
comitant ring contraction reaction, which is almost
always a side-product in the hydrogenolysis of
these 4-iodo derivatives [10]. The fear of hydrolysis
of the methyl glycoside in 8 during glycosylations
turned out to be more or less without justi®cation.
Using ordinary conditions (0.6 equiv of base) for a
silver tri¯ate-promoted glycosylation, with 2,4,6-
tri-O-benzoyl-3-deoxy-ꢀ-d-arabino-hexopyranosyl
chloride (4) (prepared from the methyl glycoside as
Although a 2-deoxy acceptor had been used with
success in the earlier synthesis of the 2,30-dideoxy
analogue [2], the supposed further enhanced acid
lability of 2,4-dideoxy glycosides [6] made us ®rst
try di€erent pathways to the target structures in
which the deoxy functions on the central moiety
were planned to be introduced as late as possible
and preferably at the trisaccharide level after gly-
cosylations with their acidic conditions. However,
all these attempts failed since the deoxygenation of
the various selectively protected trisaccharide
structures proved not to be possible. For example,
the 2-hydroxyl group in trisaccharide 5, con-
structed from the known 4-deoxy monosaccharide
precursor 1 [7] by two subsequent glycosylations
using halide donors and silver tri¯uoromethane-
sulfonate (tri¯ate) promotion (Scheme 1), proved
to be inert both to treatment with triphenylphos-
Scheme 1.
Scheme 2.

S. Oscarson, P. Svahnberg/Carbohydrate Research 309 (1998) 207±212
described for the corresponding acetylated analo- 1. Experimental
209
gue [11]) as donor and 8 as acceptor, a 65% yield
of the trisaccharide 9 was obtained. Debenzoyla-
tion using methanolic sodium methoxide then gave
the ®rst target compound 10 (73%).
General methods.ÐTLC was carried out on
Merck precoated 60 F254 plates using UV light
and/or 8% H2SO4 for visualization. Column chro-
matography was performed on silica gel (0.040±
0.063 mm, Amicon). NMR spectra were recorded
in CDCl3 (internal Me4Si, ꢁ 0.00) or D2O (internal
For the synthesis of the tetradeoxy analogue, a
3,4-dideoxy donor ®rst had to be synthesised
(Scheme 3). To obtain a 2,6-protected mannose
derivative a simple one pot-procedure was used
[12]. Treatment of methyl ꢀ-d-mannopyranoside
with triethylorthobenzoate and acid catalysts gave
the 2,3;4,6-diorthoester derivative, which was
immediately treated with aqueous tri¯uoroacetic
acid to open up the orthoesters and give a mixture
of the 2,4- and the 2,6-di-O-benzoyl derivatives 11
and 12 (45 and 34%, respectively), which could
easily be separated on a silica gel column. Use of
orthoacetates instead of benzoates could give a
better yield of the desired 2,6-acyl protected com-
pound, owing to acid-catalyzed 4- to 6-acetyl
migration [13]. However, when this was tried it was
found that other acetyl migrations were as fast and
a complex mixture of products was obtained.
Compound 12 was treated with the triphenylphos-
phine-triiodoimidazole reagent [14] to give the 3,4-
unsaturated derivative 13 (47%), which was
hydrogenated to yield the 3,4-dideoxy compound
14 (60%).
ꢀ
acetone 13C ꢁ 31.0, H ꢁ 2.21) at 25 C. Optical
rotations were determined at room temperature
with a Perkin±Elmer 241 polarimeter. Organic
phases were dried over Na2SO4 before concentra-
tion, which was performed under reduced pressure.
Methyl (2,4,6-tri-O-benzoyl-3-deoxy-a-d-arabino-
hexopyranosyl)-(1!3)-[(2,3,4,6-tetra-O-benzoyl-
a-d-mannopyranosyl)-(1!6)]-4-deoxy-a-d-lyxo-
hexopyranoside (5).ÐSilver tri¯ate (869 mg,
3.38 mmol) dissolved in dry toluene (10 mL) was
added at 0 ꢀC to a stirred solution of 1 [7] (434 mg,
1.99 mmol) and benzobromomannose (1.70 g,
2.58 mmol) in CH2Cl2 (50 mL) containing 4 A cru-
shed molecular sieves. After 1 h, NEt3 (3 mL) was
added and the stirring was continued for 15 min,
whereafter the mixture was diluted with CH2Cl2,
®ltered through Celite, concentrated, and puri®ed
by silica gel chromatography (9:1 toluene±EtOAc)
to give crude 2 (1.36 g, 86%), which was directly
treated with 90% CF3COOH for 2 h at 0 ꢀC before
concentration. Co-concentration twice with
toluene followed by silica gel chromatography (1:2
toluene±EtOAc) of the residue a€orded methyl
(2,3,4,6-tetra-O-benzoyl-ꢀ-d-mannopyranosyl)-
(1!6)-4-deoxy-ꢀ-d-lyxo-hexopyranoside (3; 1.15 g,
90%). 13C NMR: ꢁ 30.8 (C-4), 55.2 (OMe), 63.0,
65.8, 67.0, 67.2, 69.0, 70.1, and 70.7 (C-2,3,5,6,20±60),
97.4 and 101.5 (C-1,10), 128.4±133.7 (Ph), 165.6±
166.3 (PhCO). Silver tri¯ate (40 mg, 0.16 mmol)
1
Transformation of the methyl glycoside 14 into
the glycosyl chloride donor 15 was performed
using zinc chloride and dichloromethyl methyl
ether [11,15] and immediately before the coupling
to acceptor 8. Once more a good yield (51%) of the
coupling product (16) was obtained using silver
tri¯ate as a promoter (Scheme 2). The one-step
deprotection of 16 then gave the tetradeoxy target
product 17 (77%).
Scheme 3.

210
S. Oscarson, P. Svahnberg/Carbohydrate Research 309 (1998) 207±212
dissolved in dry toluene (2 mL) was added at
30 ꢀC to a stirred solution of 3 (70 mg,
0.093 mmol) and 2,4,6-tri-O-benzoyl-3-deoxy-ꢀ-d-
arabino-hexopyranosyl chloride [11] (4; 55 mg,
0.11 mmol) in CH2Cl2 (5 mL) containing crushed
4 A molecular sieves. After 2 h, NEt3 (0.2 mL) was
added and the stirring was continued for 15 min.
The mixture was diluted with CH2Cl2, ®ltered
through Celite, concentrated, and puri®ed by silica
gel chromatography (6:1 toluene±EtOAc) to give 5
(44 mg, 39%) together with unreacted 3 (18 mg,
26%). 13C NMR: ꢁ 27.3 and 29.6 (C-4,30), 55.2
(OMe), 63.0, 64.1, 65.7, 67.1, 67.3, 68.4, 69.0, 69.6,
70.1, 70.3, 70.7, and 72.9 (C-2,3,5,6,20,40±60,200±600),
95.2, 97.4, and 101.5 (C-1,10,100), 128.5±133.6 (Ph),
165.6±166.5 (PhCO).
Methyl (2,3,4,6-tetra-O-benzoyl-a-d-mannopyr-
anosyl)-(1!6)-2,4-dideoxy-a-d-threo-hexopyrano-
side (8).ÐTriphenylphosphine (0.51 g, 1.94 mmol)
and triiodoimidazole (0.43 g, 0.97 mmol) were
added to solution of 6 [2] (0.63 g, 0.65 mmol) in
toluene (10 mL). The mixture was heated to 110 ꢀC
and stirred overnight, then diluted with toluene,
washed with aq Na2S2O3 and water, dried, and
concentrated. The residue was puri®ed by silica gel
chromatography (19:1 toluene±EtOAc) to give
166.2 (PhCO). Anal. Calcd for C41H40O13: C,
66.48; H, 5.44. Found: C, 66.59; H, 5.48.
Methyl (3-deoxy-a-d-arabino-hexopyranosyl)-
(1!3)-[(a-d-mannopyranosyl)-(1!6)]-2,4-dideoxy-
a-d-threo-hexopyranoside (10).ÐSilver tri¯ate
(24 mg, 93 mmol) dissolved in dry toluene (1 mL)
ꢀ
was added at 20 C to a stirred solution of 8
(40 mg, 54 ꢂmol), 2,6-di-tert-butylpyridine (12 ꢂL,
0.054 mmol), and 4 (40 mg, 81 ꢂmol) in CH2Cl2
(2 mL) containing crushed 4 A molecular sieves.
After 1.5 h, NEt3 (200 ꢂL) was added and the stir-
ring was continued for 15 min. The mixture was
diluted with CH2Cl2, ®ltered through Celite, con-
centrated, and the residue was puri®ed by silica gel
chromatography (9:1 toluene±EtOAc) to give
methyl (2,4,6-tri-O-benzoyl-3-deoxy-ꢀ-d-arabino-
hexopyranosyl)-(1!3)-[(2,3,4,6-tetra-O-benzoyl-ꢀ-
d-mannopyranosyl)-(1!6)]-2,4-dideoxy-ꢀ-d-threo-
hexopyranoside (9; 42 mg, 65%); [ꢀ]d +16ꢀ (c 1.0,
CHCl3); 13C NMR (CDCl3): ꢁ 29.7, 33.6, and 37.5
(C-2,4,30), 55.0 (OMe), 63.2, 64.2, 65.9, 66.9, 67.3,
69.2, 69.5, 70.3, 70.4, and 70.7 (C-3,5,6,20,40±60, 200±
600), 94.9, 97.5, and 99.2 (C-1,10,100), 128.6±133.7
(Ph), 165.7±166.4 (PhCO). A solution of 9 (42 mg,
35 ꢂmol) in MeOH (5 mL) was treated with a cat-
alytic amount of 1 M methanolic NaOMe at room
temperature overnight. Dowex 50 (H+) ion-
exchange resin was added and the mixture was
then ®ltered and concentrated. Puri®cation on a
Bio-Gel P-2 column gave, after freeze-drying, 10
(12 mg, 73%); [ꢀ]d +139ꢀ (c 0.7, H2O); NMR
(D2O): 13C, ꢁ 33.0, 34.2, and 36.8 (C-2,4,30), 55.1
(OMe), 61.7, 61.8, 62.2, 67.5, 67.6, 68.2, 69.5, 69.7,
70.7, 71.3, 73.6, and 74.7 (C-3,5,6,20,40±60,200±600),
methyl
(2,3,4,6-tetra-O-benzoyl-ꢀ-d-mannopyr-
anosyl)-(1!6)-3-O-benzyl-2,4-dideoxy-2,4-diiodo-
ꢀ-d-galactopyranoside (7; 0.63 g, 90%). [ꢀ]d +50ꢀ
(c 1.0, CHCl3); 13C NMR: ꢁ 30.3 and 39.6 (C-2,4),
55.9 (OMe), 63.2, 66.9, 67.4, 69.2, 69.9, 70.3, 71.3,
72.4, and 75.0 (C-3,5,6,20±60, CH2Ph), 97.1 and
100.8 (C-1,10), 127.7±136.7 (Ph), 165.4, 165.5, and
166.2 (PhCO). Compound 7 (250 mg, 0.23 mmol)
was dissolved in 6:6:1 EtOAc±MeOH±water
(13 mL), and solid NaHCO3 (125 mg) and Pd-C
(10%) were added. The solution was hydro-
genolyzed at 100 psi for 4 h, whereafter the mixture
was ®ltered through Celite and concentrated. The
residue was dissolved in CH2Cl2, and the solution
was washed twice with aq sat Na2S2O3, dried, and
concentrated. The residue was redissolved in 1:1
EtOAc±MeOH (12 mL) and water (10 drops).
Then, Amberlite OH ion-exchange resin (250 mg)
and new Pd-C catalyst were added, and the mix-
ture was hydrogenolyzed overnight, then ®ltered
through Celite, dried, and concentrated. Silica gel
chromatography (5:1 toluene±EtOAc) gave 8
(72 mg, 42%); [ꢀ]d 29ꢀ (c 0.9, CHCl3); 13C NMR
(CDCl3): ꢁ 36.8 and 39.1 (C-2,4), 54.8 (OMe), 62.9,
63.8, 66.8, 67.0, 68.9, 70.0, and 70.5 (C-3,5,6,20±60),
97.3 and 99.1 (C-1,10), 128.3±133.5 (Ph), 165.5 and
97.2, 99.8, and 100.2 (C-1,10,100); H, ꢁ 1.46 (1 H,
1
H-4ax), 1.69 (1 H, H-2ax), 1.81 (1 H, H-30ax),
2.02±2.21 (3 H, H-2eq,30eq,4eq), 4.87 (2 H), 4.98 (1
H) (H-1,10,100). FABMS: m/z 471.3 [M+1].
Methyl 2,6-di-O-benzoyl-3,4-dideoxy-a-d-threo-
hexopyranoside
(14).Ð4-Toluenesulfonic
acid
(1.0 mL, 10% in MeCN, 0.31 mmol) and
CF3COOH (30 ꢂL, 0.39 mmol) were added to a
stirred suspension of methyl ꢀ-d-mannopyranoside
(1.0 g, 5.15 mmol) and triethylorthobenzoate
(3.0 mL, 13.4 mmol) in MeCN (75 mL). After 1 h,
the solution was concentrated and the residue dis-
solved in MeCN (50 mL). Aq 90% CF3COOH
(1.8 mL) was added and the mixture was stirred for
30 min, whereafter concentration and silica gel
chromatography (3:1 toluene±EtOAc) of the resi-
due yielded, ®rst, methyl 2,4-di-O-benzoyl-ꢀ-d-
mannopyranoside (11; 0.93 g, 45%); [ꢀ]d 48.7ꢀ

S. Oscarson, P. Svahnberg/Carbohydrate Research 309 (1998) 207±212
211
(c 1.4, CHCl3); NMR data: 13C, ꢁ 55.3 (OMe), 61.5
(C-6), 68.5, 70.3, 70.5, and 72.8 (C-2±5), 98.6 (C-1),
128.5±133.6 (Ph), 166.1 and 167.2 (PhCO); H, ꢁ
(32 mg, 0.124 mmol) dissolved in dry toluene
ꢀ
(1 mL) was added at 0 C to a stirred solution of 8
1
(54 mg, 0.073 mmol), 15 (41 mg, 0.11 mmol) and
2,6-di-tert-butylpyridine (49 ꢂL, 0.22 mmol) in
CH2Cl2 (5 mL) containing crushed 4 A molecular
sieves. After 30 min NEt3 (0.3 mL) was added and
stirring was continued for 15 min. The mixture was
diluted with CH2Cl2, ®ltered through Celite, and
evaporated. Silica gel chromatography (90:9:1
toluene±EtOAc±pyridine) gave the crude tri-
saccharide methyl (2,6-di-O-benzoyl-3,4-dideoxy-
ꢀ-d-threo-hexopyranosyl)-(1!3)-[(2,3,4,6-tetra-O-
benzoyl-ꢀ-d-mannopyranosyl)-(1!6)]-2,4-dideoxy-
ꢀ-d-threo-hexopyranoside (16; 40 mg, 51%); 13C
NMR (CDCl3): ꢁ 22.0 and 22.8 (C-30,40), 33.4 and
37.3 (C-2,4), 54.7 (OMe), 62.9, 66.6, 67.0, 67.1,
67.3, 68.3, 68.9, 69.3, 70.0, 70.2, and 70.4 (C-
3,5,6,20,50,60,200±600), 95.2, 97.1, and 99.0 (C-1,10,100),
128.3±133.4 (Ph), 165.4±166.6 (PhCO), which was
deprotected following the same protocol as descri-
bed for compound 9. Puri®cation on a Bio-Gel P-2
column gave, after freeze-drying, 17 (13 mg, 77%);
[ꢀ]d +130ꢀ (c 1.3, H2O); NMR (D2O): 13C, ꢁ 21.1,
24.7, 33.1, and 36.8 (C-2,4,30,40), 55.1 (OMe), 61.7,
65.1, 65.9, 67.5, 67.7, 69.3, 69.7, 70.7 (2 C), 71.3,
and 73.6 (C-3,5,6,20,50,60ꢀ,200±600), 98.0, 99.8, and
3.77 (2 H, H-6a,6b), 3.92 (1 H, H-5), 4.41 (1 H, H-
3), 4.92 (1 H, H-1), 5.41 (1 H, H-2), 5.48 (1 H, H-
4); followed by methyl 2,6-di-O-benzoyl-ꢀ-d-man-
nopyranoside (12; 0.70 g, 34%); [ꢀ]d +10.8ꢀ (c 0.9,
CHCl3); NMR data: 13C, ꢁ 55.2 (OMe), 63.6 (C-6),
67.9, 70.0, 70.7, and 72.3 (C-2±5), 98.8 (C-1),
1
128.4±133.3 (Ph), 166.1 and 167.1 (PhCO); H, ꢁ
3.91 (2 H, H-4,5), 4.15 (1 H, H-3), 4.53 (1 H, H-
6a), 4.83 (2 H, H-1,6b), 5.37 (1 H, H-2). Triphe-
nylphosphine (1.49 g, 5.67 mmol), imidazole
(0.39 g, 5.67 mmol) and iodine (1.08 g, 4.25 mmol)
were added to a solution of 12 (0.57 g, 1.42 mmol)
in toluene (100 mL). The mixture was heated to
ꢀ
110 C and stirred overnight, then diluted with
toluene, washed with aq Na2S2O3 and water, dried,
and concentrated. The residue was puri®ed by
silica gel chromatography (9:1 toluene±EtOAc) to
give methyl 2,6-di-O-benzoyl-3,4-dideoxy-ꢀ-d-
threo-hex-3-enopyranoside (13, slightly con-
taminated; 0.25 g, 47%); [ꢀ]d +58ꢀ (c 1.1, CHCl3);
13C NMR (CDCl3): ꢁ 56.1 (OMe), 65.5, 65.6, and
66.5 (C-2,5,6), 98.9 (C-1), 122.3 and 131.4 (C-3,4),
128.4±133.2 (Ph), 165.4 and 165.8 (PhCO). Com-
pound 13 (0.60 g, 1.63 mmol) was dissolved in 6:6:1
EtOAc±MeOH±water (13 mL), and Pd-C (10%)
was added. The solution was hydrogenolyzed at
100 psi overnight, then ®ltered, concentrated, and
redissolved in 6:6:1 EtOAc±MeOH±water (13 mL).
Some new catalyst was added and the solution was
hydrogenolyzed for another night, then ®ltered
through Celite, dried, and concentrated. Silica gel
chromatography (50:1 toluene±EtOAc) of the resi-
due gave 14 (0.36 g, 60%); [ꢀ]d +51ꢀ (c 0.9,
CHCl3); 13C NMR (CDCl3): ꢁ 22.0 and 22.9 (C-
3,4), 54.9 (OMe), 66.7, 67.2, and 67.8 (C-2,5,6),
98.1 (C-1), 128.4±133.1 (Ph), 165.7 and 166.4
(PhCO). Anal. Calcd for C21H22O6: C, 68.10; H,
5.99. Found: C, 68.05; H, 6.06.
0
00
1
100.2 (C-1,1 ,1 ); H (70 C), ꢁ 1.35±2.22 (8 H, H-
2ax,2eq,30ax,30eq,4ax,4eq,40ax,40eq), 4.87 (1 H) and
4.96 (2 H) (H-1,10,100). FABMS: m/z 455.3 [M+1].
Acknowledgements
The authors thank Professor Per J. Garegg for
his interest in this work and the Swedish Natural
Science Research Council for ®nancial support.
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