3.30 (m, 1 H, H-5), 3.27 (dd, 1 H, J ) 9.6, 8.0 Hz, H-2), 2.97 (d,
1 H, J ) 6.0 Hz, OH-3′), 2.81 (d, 1 H, J ) 2.0 Hz, OH-2′), 2.71
(d, 1 H, J ) 3.6 Hz, OH-4′). HRESIMS calcd for C45H59O10N3Si2
[M + NH4]+ 875.4083, found 875.4047.
TMSOTf (Table 2, entries 4 and 5) led to the conversion of
trichloroacetimidate 11 to the glucal 15 that, in turn, underwent
Ferrier-type glycosidation by the acceptor 10 to give trisac-
charide 13. Although Ferrier rearrangement reactions with
2-phthalimido-D-glucal have been described15 and such glucals
have been isolated during glycosylation reactions,16 this is, to
our knowledge, the first report of the formation of a Ferrier
rearrangement product during the glycosylation of a saccharide
acceptor with a 2-deoxy-2-phthalimido-glucosyl donor.
Methyl 3-O-Acetyl-4-O-[2,4-di-O-acetyl-6-O-tert-butyldiphen-
ylsilyl-3-O-(3,4,6-tri-O-acetyl-2-deoxy-2-N-phthalimido-â-D-
glucopyranosyl)-â-D-galactopyranosyl]-2-azido-6-O-tert-butyldi-
phenylsilyl-2-deoxy-â-D-glucopyranoside (12) and Methyl 3-O-
Acetyl-4-O-[2,4-di-O-acetyl-3-O-(4,6-di-O-acetyl-2,3-dideoxy-2-
N-phthalimido-R-D-erythro-hex-2-eno-pyranosyl)-6-O-tert-bu-
tyldiphenylsilyl-â-D-galactopyranosyl]-2-azido-6-O-tert-butyl-
diphenylsilyl-2-deoxy-â-D-glucopyranoside (13). The disaccharide
acceptor 10 (97 mg, 0.1 mmol) and the donor 11 (171 mg, 3.0
equiv) were dissolved in anhydrous CH2Cl2 (10 mL) and predried
with MS 4 Å (500 mg, 50 mg/mL) for 2 h under N2. The mixture
was cooled down to -30 °C, and freshly distilled TMSOTf (54
µL, 3.0 equiv) was added. The reaction mixture was kept at -24
°C overnight, triethylamine was added, and the molecular sieves
were filtered off through glass wool. The solids were washed with
CH2Cl2 (5 mL), and the combined filtrate and washings were
concentrated. Flash chromatography (EtOAc/hexanes, 1:1) of the
residue and further purification with centrifugal chromatography
(EtOAc/hexanes, 1:1) gave a mixture of trisaccharides 12 and 13
(100 mg, 12/13 ) 1:1 by NMR integration, 72%). Further
purification by reverse phase HPLC (H2O/CH3CN, 20:80 to 0:100)
gave the pure trisaccharides 12 (28 mg, 20%) and 13 (33 mg, 25%).
Although the formation of trisaccharide 13 decreased the yield
of the desired trisaccharide 12, we were able to isolate sufficient
amounts of 12 to proceed with its deprotection to obtain trisac-
charide 2. Thus trisaccharide 12 was treated with fluoride ions
to remove the silyl groups, and the resulting diol was submitted
to Zemple´n deacetylation. The phthalimido group was removed
with ethylene diamine, and the resulting trisaccharide still
carrying an azido group at C-2 was reduced (H2, Pd/C in MeOH)
and selectively N-acetylated in situ at both amino groups with
acetic anhydride. The final trisaccharide 2 was purified by flash
silica gel and Biogel P2 chromatography successively and was
obtained in a 47% yield over the four steps of deprotection.
The dimLex trisaccharide fragment GlcNAc-â-(1f3)-Gal-â-
(1f4)-GlcNAc-â-(1fO)-Me (2) was synthesized. A key inter-
mediate to our synthesis was the selectively disilylated 2-deoxy-
2-azido lactose derivative 5. Although the selective enzymatic
acetylation of OH-6 and OH-6′ on a similar disaccharide has
been reported,17 we are describing here, to the best of our know-
ledge, the first selective chemical protection of the primary hy-
droxyl groups in a 2-azido â-lactoside. Indeed, as we and others9
have observed, the reactivity of the galactosyl OH-3′ in lactose
derivatives often leads to the concomitant protection of O-6,
O-6′, and O-3′. It is also interesting to point out that although
silylation at O-6 and O-6′ of an R-benzyl glycoside of N-acetyl-
lactosamine has been reported11c in good yields (82%), only
mediocre (42%) yields have been reported11b for a similar reac-
tion carried out on the analogous â-allyl glycoside. We also
report that using high concentration of TMSOTf to catalyze a
glycosylation employing a 2-deoxy-2-phthalimido glucosyl
donor may lead to the formation of a Ferrier rearrangement
oligosaccharide. However, the desired trisaccharide fragment
2 could be prepared in sufficient quantities to be used in NMR
studies to assess its conformational behavior as well to be em-
ployed as competing antigen in immunological binding experi-
ments. These further studies are ongoing on our laboratory.
1
Analytical data for 12: [R]D ) 3° (c 1.5, CHCl3). Selected H
NMR (400 MHz, CDCl3): δ 5.83 (dd, 1 H, J ) 10.0, 9.2 Hz, H-3′′),
5.48 (d, 1 H, J ) 3.6 Hz, H-4′), 5.40 (d, 1 H, J ) 8 Hz, H-1”),
5.18 (t, 1 H, J ≈ 9.5 Hz, H-4′′), 4.84 (t, 1 H, J ≈ 10.0 Hz, H-3),
4.77 (dd, 1 H, J ) 10.0, 8.0 Hz, H-2′), 4.64 (d, 1 H, J ) 8 Hz,
H-1′), 4.29 (dd, 1 H, J ) 12.4, 2.8 Hz, H-6′′), 4.23-2.20 (m, 1 H,
H-6b′′), 4.21-4.18 (m, 1 H, H-2′′), 4.15 (d, 1 H, J ) 8 Hz, H-1),
3.96 (t, 1 H, J ) ∼9.5 Hz, H-4), 3.90-3.84 (m, 3 H, H-6a, H-6b,
H-5′′), 3.69 (dd, 1 H, J ) 10.0, 3.6 Hz, H-3′), 3.63-3.56 (m, 3 H,
H-5′, H-6a′, H-6b′), 3.54 (s, 3 H, CH3O), 3.34 (dd, 1 H, J ) 10.0,
8.0 Hz, H-2), 3.17 (d, 1 H, J ) 9.6 Hz, H-5). HRESIMS calcd for
C71H84O22N4Si2 [M + Na]+ 1423.5013, found 1423.4960. Analyti-
1
cal data for 13: [R]D ) 39° (c 1.1, CHCl3). Selected H NMR
(300 MHz, CDCl3): 6.07 (s, 1 H, H-3′′), 5.83 (s, 1 H, H-1′′), 5.58
(d, 1 H, J ) 9.6 Hz, H-4′′), 5.28 (d, 1 H, J ) 2.7 Hz, H-4′), 4.98-
4.89 (m, 2 H, H-3, H-2′), 4.62 (d, 1 H, J ) 8.0 Hz, H-1′), 4.39
(dd, 1 H, J ) 12.3, 1.8 Hz, H-6a′′), 4.22-4.16 (m, 2 H, H-1, H-6b′′),
4.10-4.02 (m, 1 H, C-5′′), 4.05-3.95 (m, 1 H, H-4), 4.02-3.88
(m, 2 H, H-6a, H-6b), 3.94-3.83 (m, 1 H, H-3′), 3.68-3.58 (m, 1
H, H-6a′), 3.60-3.52 (m, 1 H, H-5′), 3.53 (s, 3 H, CH3O), 3.48-
3.40 (m, 1 H, H-6b′), 3.42-3.33 (m, 1 H, H-2), 3.38-3.28 (m, 1
H, H-5). Selected 13C NMR (75 MHz, CDCl3): δ 129.4 (C-2′′),
∼128.0 (C-3′′), 102.5 (C-1), 100.3 (C-1′), 92.7 (C-1′′). HRESIMS
calcd for C69H80O20N4Si2 [M + NH4]+ 1358.5248, found 1358.5237.
Experimental Section
Acknowledgment. We thank the National Science and
Engineering Research Council of Canada, the Canada Founda-
tion for Innovation, and the Ontario Innovation Trust for
financial support of this work. F.-I. A. is also grateful to the
Ontario Ministry of Research and Innovation for a Premier’s
Research Excellence Award.
Methyl 2-Azido-6-O-tert-butyldiphenylsilyl-4-O-(6-O-tert-bu-
tyldiphenylsilyl-â-D-galactopyranosyl)-2-deoxy-â-D-glucopyra-
noside (5). TBDPSCl (37 µL, 2.2 equiv) was added to a solution
of disaccharide 3 (25 mg, 66 µmol) in DMF (2 mL) containing
imidazole (27 mg, 6.0 equiv) and stirred under N2. The reaction
mixture was stirred at room temperature for 1 h, more TBDPSCl
(17 µL, 1.0 equiv) was added, and the reaction was allowed to
proceed for 2 days at room temperature. The solvent was evapo-
rated, and the residue was co-concentrated with toluene (3 × 5
mL). Flash chromatography of the residue (EtOAc/hexanes, 1:9 to
3:7 to 7:3) gave first the trisilylated product 6 (5 mg, 7%) and then
the disilylated product 5 (46 mg, 82%). [R]D ) -13° (c 3.8, CHCl3).
Selected 1H NMR (400 MHz, CDCl3): δ 4.45 (d, 1 H, J ) 8.0 Hz,
H-1′), 4.26 (s, 1 H, OH-3), 4.10 (d, 1 H, J ) 8.0 Hz, H-1), 4.03
(dd, 1 H, J ) 12.0, 3.2 Hz, H-6a), 3.99 (m, 1 H, H-4′), 3.93-3.88
(m, 2 H, H-6b, H-6b′), 3.83 (dd, 1 H, J ) 10.5, 6.0 Hz, H-6a′),
3.74 (t, 1 H, J ≈ 9 Hz, H-4), 3.64 (m, 1 H, H-2′), 3.58 (m, 1 H,
H-5′), 3.56-3.49 (m, 2 H, H-3, H-3′), 3.52 (s, 3 H, CH3O), 3.33-
Supporting Information Available: General experimental
procedures and preparation of compounds 4, 5, and 6 (TBDPSCl/
1
DMF AgNO3), 7, 10, 12, and 2. Additional listing of H and 13C
1
NMR data for 5, 12, and 13. H, and Jmod spectra for 2 in D2O
and 4-7, 10, 12, 13 in CDCl3. This material is available free of
JO062541Y
(17) La Ferla, B.; Lay, L.; Russo, G.; Panza, L. Tetrahedron: Asymmetry
2000, 11, 3647-3651. La Ferla, B.; Prosperi, D.; Lay, L.; Russo, G.; Panza,
L. Carbohydr. Res. 2002, 337, 1333-1342.
3588 J. Org. Chem., Vol. 72, No. 9, 2007