Regioselective glycosylation of 3,6-unprotected mannoside derivatives: Fast access to high-mannose type oligosaccharides

Article abstract of DOI:10.1016/j.tetlet.2003.09.219

A regioselective glycosylation of 3,6-unprotected mannoside acceptors was investigated. With glycosyl trichloroacetimidate donors, when an excess of trimethylsilyl trifluoromethanesulfonate is used as the catalyst, 6-O-glycosylation exclusively occurred affording a silylated disaccharide that could be involved in a subsequent glycosylation reaction. As an illustration, the fast synthesis of two trisaccharides and one pentasaccharide was achieved.

Full text of DOI:10.1016/j.tetlet.2003.09.219

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8999–9002
Regioselective glycosylation of 3,6-unprotected mannoside
derivatives: fast access to high-mannose type oligosaccharides
Nicolas Smiljanic, Sami Halila, Vincent Moreau* and Florence Djeda¨ıni-Pilard
Laboratoire des Glucides, Universite´ Picardie Jules Verne, 33 rue St-Leu, 80039 Amiens, France
Received 4 September 2003; revised 24 September 2003; accepted 30 September 2003
Abstract—A regioselective glycosylation of 3,6-unprotected mannoside acceptors was investigated. With glycosyl trichloroacetim-
idate donors, when an excess of trimethylsilyl trifluoromethanesulfonate is used as the catalyst, 6-O-glycosylation exclusively
occurred affording a silylated disaccharide that could be involved in a subsequent glycosylation reaction. As an illustration, the
fast synthesis of two trisaccharides and one pentasaccharide was achieved.
© 2003 Elsevier Ltd. All rights reserved.
As part of our research towards the synthesis of man-
nosyl mimetic derivatives based on a b-cyclodextrin
(b-CD) core,1 a short and effective route was required
for the preparation of high-mannose type oligosaccha-
rides found in the HIV-1 viral surface envelope glyco-
protein gp 120.
when an excess of trimethylsilyl trifluoromethanesul-
fonate (TMSOTf) is used as the catalyst.
Owing to the known versatility of glycosyl trichloroace-
timidate in glycosylation reactions,8 we chose to employ
2,3,4,6-tetra-O-benzoyl-a-
acetimidate9 1 and 2-O-acetyl-3,4,6-tri-O-benzoyl-a-
mannopyranosyl trichloroacetimidate10 2. As methyl
-mannopyranose is commercially available, the
D-mannopyranosyl trichloro-
D
-
Some successful syntheses of the HIV-1 nonamannoside
structure have been achieved, notably by Fraser-Reid,2
Ley3 and more recently by Seeberger.4 The latter pre-
sents a powerful linear synthesis based on a simulta-
neous multi-glycosylation strategy. Nevertheless, the
assembly of the starting differentially protected triman-
noside requires a relatively long multistep procedure.
The use of the trityl-cyanoethylidene condensation as a
glycosylation method developed by Backinowsky et al.5
could circumvent this drawback. This procedure in
which selective 3-O-glycosylation of 3,6-di-O-trityl
mannoside acceptors occurs in good yield with 1,2-O-
a-D
methyl 2,4-di-O-benzoyl-a-D-mannopyranose 3 was
chosen as acceptor.
The recently described synthesis of the known 2-O-acet-
yl-3,4,6-tri-O-benzoyl-a-D-mannopyranosyl trichloro-
acetimidate 2,10 was slightly modified (Scheme 1).
The key intermediate diol, namely 3,4,6-tri-O-benzoyl-
D
-mannopyranose 5, was obtained in three steps from
the per-O-benzoyl- -mannopyranose via the 3,4,6-tri-
O-benzoyl-1,2-O-benzylidene-b- -mannopyranose 4.
D
[(1-cyano)ethylidene]-b-D-mannopyranose donors, and
has been utilised for the convergent synthesis of ‘fully-
carbohydrate’ mannodendrimers.6
D
Nevertheless, the easy access to 3,6-unprotected man-
noside derivatives described by Bundle7 prompted us to
investigate a regioselective glycosylation approach. We
report here the results of our study which show that
6-O-glycosylation can be highly regioselective and
effective with glycosyl trichloroacetimidate donors
Keywords: regioselective glycosylation; high-mannose.
* Corresponding author. Tel.: +33 (0) 3 22 82 76 61; fax: +33 (0) 3 22
82 75 62; e-mail: vincent.moreau@sc.u-picardie.fr
Scheme 1. Reagents and conditions: (i) HBr/AcOH, CH2Cl2,
2 h then Bu4NI, NaBH4, CH3CN, 36 h; (ii) HBF4/H2O,
CH3CN, 4 h, 45% (2 steps).
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.219

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N. Smiljanic et al. / Tetrahedron Letters 44 (2003) 8999–9002
The latter was prepared using the classical method11 in
45% yield, followed by hydrolysis of the ketal with 50%
aq. tetrafluoroboric acid to afford the diol 5 in quanti-
tative yield.
Because of these relatively disappointing results, we
decided to investigate the influence of the amount of
the catalyst. Using a large excess of TMSOTf (3.5
equiv.) at −80°C led to the methyl 2,4-di-O-benzoyl-3-
O-trimethylsilyl-6-O-(2,3,4,6-tetra-O-benzoyl-a-
D-manno-
pyranosyl)-a-
D
-mannopyranose12 10 in 70% yield. It is
As shown in Scheme 2, the acceptor 3 was prepared in
a one-pot procedure. Methyl a-D-mannopyranose was
reacted with triethyl orthobenzoate in the presence of
camphorsulfonic acid (CSA) as a catalyst. The 2,3,4,6-
di-O-orthoester intermediate thus obtained was
hydrolysed with aq. trifluoroacetic acid (1:9) to give a
mixture of the corresponding 2,4- and 2,6-di-O-benz-
notable that the silylation occurred after the quenching
of the reaction mixture with triethylamine. Therefore,
the amount of the promotor did not play a part in the
regioselectivity but only increased the rate of the reac-
tion. Under these conditions, a small amount of trisac-
charide 9 was formed (10%).
oates, namely methyl 2,4-di-O-benzoyl-a-
D
-mannopy-
-mannopy-
Moreover, glycosylation of the disaccharide 10 with the
donor 2 in the presence of an excess of TMSOTf (3.5
equiv.) can be performed without prior deprotection of
the silylated hydroxy group in quite good yield (55%) to
give the differentially protected trimannoside
derivative13 11 (Scheme 3). It should be pointed out
that under these conditions, but in the absence of
donor, the disaccharide 10 led to the desilylated deriva-
tive 7. We concluded that the glycosylation of 10 with
the donor 2 followed an in situ cleavage of the silyl
ether with the Lewis acid.
ranoside 3 and methyl 2,6-di-O-benzoyl-a-
D
ranoside 6 in 29% and 24% yields, respectively. Both
compounds were readily separated by flash chromato-
graphy.
The utility of our approach was demonstrated through
the synthesis of a pentasaccharidic fragment of a high-
mannose type oligosaccharide (see Scheme 5).
Scheme 2. Reagents and conditions: (i) triethyl orthobenzoate,
CSA, CH3CN, 2 h; (ii) 90% CF3CO2H, CH3CN, 10 min, 29%
of 3 (2 steps).
Keeping in mind that the oligosaccharidic part of our
mannosyl mimetic derivatives based on a b-cyclodextrin
core is linked through a peptidic bond to the b-CD,1
First attempts at glycosylation between the donor 1 and
the acceptor 3 were performed using standard condi-
tions (low temperature, 0.5 equiv. of TMSOTf, CH2Cl2,
N2 atmosphere, 1.2 equiv. of 1). We presumed that
using a low temperature would increase the difference
in reactivity between the primary hydroxy group and
the secondary one. Very low temperatures (−80°C and
−60°C) afforded only traces or poor yields (25% at
−60°C) of the expected a-1,6-disaccharide 7 (Scheme 3).
The best yield was obtained at −40°C (47%). Glycosyla-
tion only occurred on the primary hydroxy group. The
a-1,3-disaccharide 8 and the trisaccharide 9 were not
observed even at higher temperature.
the 2,4-di-O-benzoyl-a- -mannopyranosyl azide 12 was
D
chosen as acceptor and was obtained as previously
described.1 The azide 12 was also designed as starting
material in order to obtain a differentially protected
donor. It is known that a glycosyl azide can be con-
verted into a glycosyl fluoride donor in two steps
(40–50% overall yields) via a triazole intermediate.14
Nevertheless, we developed an alternative procedure to
obtain the 3,6-di-O-acetyl-2,4-di-O-benzoyl-a-D-manno-
pyranosyl trichloroacetimidate 15 from the azide 12, in
three steps with a good overall yield (55%) (Scheme 4).
Scheme 3. Reagents and conditions: (i) 0.5 equiv. TMSOTf, CH2Cl2, −40°C, 30 min, 47% of 7; (ii) 3.5 equiv. TMSOTf, CH2Cl2,
−80°C, 30 min, 70% of 10; (iii) 10, 1.5 equiv. donor 2, 3.5 equiv. TMSOTf, CH2Cl2, 0°C to rt, 1 h, 55%.

N. Smiljanic et al. / Tetrahedron Letters 44 (2003) 8999–9002
9001
ated disaccharide derivative 17 and 2 with an excess of
TMSOTf led to the trisaccharide18 20 in good yield
(62%).
The structures of compounds 10, 11, 18, 19 and 20 and
other intermediates were established using 1D- and
2D-NMR spectroscopy (COSY, Relays, HMQC). The
spin–spin coupling constants of vicinal protons have
values indicative of a-D-mannopyranose residues (J1,2=
1–2 Hz, J2,3=3–3.5 Hz).5,6 Moreover, the chemical
shifts of the anomeric C atoms are consistent with those
reported in the literature:6 around 97.5 ppm for the
a-(1“6) linked units and around 99.2 ppm for the
a-(1“3) linked ones.
Scheme 4. Reagents and conditions: (i) Ac2O, pyridine then
H2, Pd/C, EtOH, 20 bar, 83%; (ii) HCl 2N, NaNO2, acetone,
0°C to rt, 40 min, 73%; (iii) CCl3CN, DBU, 0°C to rt, 1 h,
90%.
It should be pointed out that the acetyl groups of 19 as
well as 20 can be selectively removed and free hydroxy
groups again simultaneously multi-glycosylated opening
a short route to hexa-, octa- and nonamannoside
derivatives of high-mannose type.
After acetylation of the free hydroxy groups, the azide
group was reduced by classical hydrogenation in quan-
titative yield. Then, the resulting amine 13 was
hydrolysed under nitrous acid catalysis to afford the
desired 3,6-di-O-acetyl-2,4-di-O-benzoyl-D-mannopy-
ranose 14. Subsequent reaction of 14 with trichloroace-
tonitrile under DBU catalysis gave the donor 15.
In summary, we have demonstrated that the glycosyla-
tion of 3,6-unprotected mannoside acceptors occurred
on the primary hydroxy group in high yield when an
excess of TMSOTf is used. This regioselective glycosyl-
ation approach leads to silylated disaccharides which
can be used as starting materials for the fast and
efficient synthesis of high-mannose type oligosaccha-
rides of variable size.
Condensation of 12 with donor 15 in the presence of a
catalytic amount of TMSOTf (0.5 equiv.) afforded the
disaccharide 16, namely 2,4-di-O-benzoyl-6-O-(3,6-di-
O-acetyl-2,4-di-O-benzoyl-a-
D
-mannopyranosyl)-a-D-
mannopyranosyl azide, in 50% yield. Once again, using
an excess of TMSOTf increased the yield up to 90%
leading to the trimethylsilylated disaccharide derivative
17. Deacetylation of 16 or simultaneous deacetylation
and desilylation of 17 were performed by acid-catalysed
methanolysis15 to afford the triol16 18 in around 65%
from both compounds. Simultaneous tri-glycosylation
of 18 with 6 equivalents of the trichloroacetimidate
donor 2 afforded the expected pentasaccharide17 19 in
70% yield. Moreover, condensation of the trimethylsilyl-
Acknowledgements
This work was supported by the Conseil Re´gional de
Picardie under the scientific IBFBio program. N. S. is
grateful to the Conseil Re´gional de Picardie for a
doctoral fellowship.
Scheme 5. Reagents and conditions: (i) 0.5 equiv. TMSOTf, CH2Cl2, −40°C, 30 min, 50% of 16; (ii) 3.5 equiv. TMSOTf, CH2Cl2,
−80°C, 30 min, 90% of 17; (iii) 16 or 17, CH3COCl, CH3OH, CH2Cl2, 24 h, 65%; (iv) 6 equiv. donor 2, 0.5 equiv. TMSOTf,
CH2Cl2, −20°C to rt, 90 min, 70%; (v) 17, 3 equiv. donor 2, 3.5 equiv. TMSOTf, CH2Cl2, 0°C to rt, 1 h, 62%.

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N. Smiljanic et al. / Tetrahedron Letters 44 (2003) 8999–9002
OCOMe). 13C NMR (75 MHz, CDCl3): l 99.4 (C-1c),
References
98.7 (C-1a), 97.4 (C-1b). ES-LRMS m/z=1519.5 [M+
Na]+.
1. Yockot, D.; Moreau, V.; Demailly, G.; Djeda¨ıni-Pilard,
F. Org. Biomol. Chem. 2003, 1, 1810–1818.
2. Merritt, J. R.; Naisang, E.; Fraser-Reid, B. J. Org. Chem.
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1994, 59, 4443–4449.
15. Byramova, N. E.; Ovchinnikov, M. V.; Backinowsky, L.
V.; Kochetkov, N. K. Carbohydr. Res. 1983, 124, C8–
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3. Grice, P.; Ley, S. V.; Pietruszka, J.; Osborn, H. M. I.;
Priepke, H. W. M.; Warriner, S. L. Chem. Eur. J. 1997, 3,
431–440.
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Grachev, A. A.; Kochetkov, N. K. Polish J. Chem. 1999,
73, 955–965.
16. Selected data for 18: 1H NMR (300 MHz, CDCl3): l
8.13–7.28 (m, 20H, OCOPh), 5.72 (t, 1H, J3,4=J4,5=9.9
Hz, H-4a), 5.66 (d, 1H, J1,2=1.7 Hz, H-1a), 5.51–5.44 (m,
2H, H-2b, H-4b), 5.35 (dd, 1H, J2,3=3.4 Hz, H-2a), 5.11
(d, 1H, J1,2=1.3 Hz, H-1b), 4.51 (dd, 1H, J2,3=3.3 Hz,
J3,4=9.7 Hz, H-3b), 4.35–4.31 (m, 2H, H-3a, H-5a), 4.01
6. Backinowsky, L. V.; Abronina, P. I.; Shashkov, A. S.;
Grachev, A. A.; Kochetkov, N. K.; Nepogodiev, S. A.;
Fraser Stoddart, J. Chem. Eur. J. 2002, 8, 4412–4423.
7. Yu, N. H.; Ling, C. C.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 2001, 832–837.
(dd, 1H, J5,6=4.2 Hz, J6,6%=11.2 Hz, H-6a), 3.83–3.76
(m, 2H, H-6%a, H-5b), 3.49–3.41 (m, 2H, H-6b, H-6%b).
13C NMR (75 MHz, CDCl3): l 97.6 (C-1b), 87.5 (C-1a).
ES-LRMS m/z=806.3 [M+Na]+.
17. Selected data for 19: 1H NMR (500 MHz, CDCl3): l
8.16–7.12 (m, 65H, OCOPh), 6.02 (t, 1H, J2,3=J3,4=10.0
Hz, H-4b), 5.90–5.54 (m, 12H, H-1a (5.66 ppm, J1,2=1.9
Hz), H-2a, H-2b, H-2c or H-2e, H-2d, H-3c, H-3d, H-3e,
H-4a, H-4c, H-4d, H-4e), 5.17 (d, 1H, J1,2<1 Hz, H-1b),
5.11 (m, 2H, H-1c or H-1e, H-2c or H-2e), 5.08 (d, 1H,
8. Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 21–123.
9. Bien, F.; Ziegler, T. Tetrahedron: Asymmetry 1998, 9,
781–790.
10. Heng, L.; Ning, J.; Kong, F. J. Carbohydr. Chem. 2001,
20, 285–296.
J
1,2=1.8 Hz, H-1c or H-1e), 4.89 (d, 1H, J1,2=1.4 Hz,
H-1d), 4.61 (dd, 1H, J2,3=3.3 Hz, H-3b), 4.56 (dd, 1H,
2,3=3.3 Hz, J3,4=10.0 Hz, H-3a), 4.53–4.14 (m, 12H,
H-5a, H-5b, H-5c, H-5d, H-5e, H-6a, H-6c, H-6d, H-6e,
H-6%c, H-6%d, H-6%e), 4.06 (dd, 1H, J5,6=4.4 Hz, J6,6%
11. Betaneli, V. I.; Ovchinnikov, M. V.; Backinowsky, L. V.;
Kochetkov, N. K. Carbohydr. Res. 1982, 107, 285–291.
12. Selected data for 10: 1H NMR (300 MHz, CDCl3): l
8.08–7.27 (m, 30H, OCOPh), 6.12 (t, 1H, J3,4=J4,5=9.8
Hz, H-4b), 6.01 (dd, 1H, J2,3=3.1 Hz, H-3b), 5.76 (dd,
1H, J1,2=1.44 Hz, H-2b), 5.74 (t, 1H, J3,4=J4,5=9.9 Hz,
H-4a), 5.48 (dd, 1H, J1,2=1.2 Hz, J2,3=3.5 Hz, H-2a),
5.14 (d, 1H, H-1b), 4.94 (d, 1H, H-1a), 4.55–4.43 (m, 3H,
H-6b, H-5b, H-3a), 4.34 (dd, 1H, J5,6=4.0 Hz, J6,6%=11.9
Hz, H-6%b), 4.23 (ddd, 1H, J5,6=5.1 Hz, J5,6%=1.9 Hz,
H-5a), 4.12 (dd, 1H, J6,6%=10.6 Hz, H-6a), 3.75 (dd, 1H,
H-6%a), 3.60 (s, 3H, OMe), 0.03 (s, 9H, SiMe3). 13C NMR
(75 MHz, CDCl3): l 99.1 (C-1a), 97.4 (C-1b). ES-LRMS
m/z=1091.4 [M+K]+.
J
=
11.2 Hz, H-6b), 3.79 (dd, 1H, J5,6<1 Hz, J6,6%=10.2 Hz,
H-6%a), 3.62 (dd, 1H, J5,6%=1.9 Hz, H-6%b), 1.97, 1.93 and
1.78 (3 s, 9H, OCOCH3). 13C NMR (125 MHz, CDCl3):
l 99.4 (C-1c or C), 98.8 (C-1c or C-1e), 97.6 (C-1b), 97.5
(C-1d), 88.5 (C-1a). ES-HRMS m/z=2354.6443 [M+Na]+
2354.6434 required.
18. Selected data for 20: 1H NMR (300 MHz, CDCl3): l
8.27–7.28 (m, 35H, OCOPh), 5.81 (t, 1H, J3,4=J4,5=9.5
Hz, H-4a), 5.77 (t, 1H, J3,4=J4,5=10.0 Hz, H-4c), 5.72–
5.69 (m, 2H, H-3b, H-4b), 5.68 (d, 1H, J1,2=2.0 Hz,
H-1a), 5.59–5.54 (m, 3H, H-2a, H-2b, H-3c), 5.17 (d, 1H,
13. Selected data for 11: 1H NMR (300 MHz, CDCl3): l
8.32–7.28 (m, 45H, OCOPh), 6.15 (t, 1H, J3,4=J4,5=10.0
Hz, H-4b), 6.01 (dd, 1H, J2,3=3.5 Hz, H-3b), 5.89 (t, 1H,
J
1,2=2.0 Hz, H-1c), 5.14 (dd, 1H, J2,3=3.3 Hz, H-2c),
5.05 (d, 1H, J1,2=1.8 Hz, H-1b), 4.50 (dd, 1H, J2,3=3.5
Hz, H-3a), 4.47–4.38 (m, 4H, H-5a, H-5c, H-6c, H-6%c),
4.30 (m, 1H, H-5b), 4.18 (d, 2H, J5,6=4.4 Hz, H-6b,
H-6%b), 4.05 (dd, 1H, J5,6=6.0 Hz, J6,6%=11.0 Hz, H-6a),
3.80 (dd, 1H, J5,6%=2.2 Hz, H-6%a), 1.92, 1.89 and 1.88 (3
s, 9H, OCOCH3). 13C NMR (75 MHz, CDCl3): l 99.7
(C-1c), 97.8 (C-1b), 88.0 (C-1a). ES-LRMS m/z=1406.2
[M+Na]+.
J
3,4=J4,5=9.9 Hz, H-4a), 5.80 (t, 1H, J3,4=J4,5=9.0 Hz,
H-4c), 5.78 (dd, 1H, J1,2=1.8 Hz, H-2b), 5.73 (dd, 1H,
1,2=1.8 Hz, J2,3=3.5 Hz, H-2a), 5.63 (dd, 1H, J2,3=3.3
J
Hz, H-3c), 5.22 (d, 1H, J1,2=2.0 Hz, H-1c), 5.20–5.16 (m,
2H, H-1b, H-2c), 5.03 (d, 1H, H-1a), 4.66–4.26 (m, 7H,
H-3a, H-5b, H-6b, H-6%b, H-5c, H-6c, H-6%c), 4.21–4.14
(m, 2H, H-5a, H-6a), 3.81 (dd, 1H, J5,6=1.8 Hz, J6,6%
10.6 Hz, H-6%a), 3.55 (s, 3H, OMe), 1.91 (s, 3H,
=