Investigations of glycosylation reactions with 2-N-acetyl-2N,3O- oxazolidinone-protected glucosamine donors

Article abstract of DOI:10.1021/jo800971s

(Chemical Equation Presented) NIS/AgOTf-promoted glycosylations with ethyl 2,3-N,O-carbonyl-2-deoxy-1-thio-β-D-glucopyranoside donors can be performed with either α- or β-selectivity by tuning the reaction conditions. Small amounts of AgOTf (0.1 equiv) an

Full text of DOI:10.1021/jo800971s

Investigations of Glycosylation Reactions with
2-N-Acetyl-2N,3O-oxazolidinone-Protected Glucosamine Donors
Johan D. M. Olsson,† Lars Eriksson,‡ Martina Lahmann,†,§ and Stefan Oscarson*,†,¶
Department of Organic Chemistry, Arrhenius Laboratory, and DiVision of Structural Chemistry, Stockholm
UniVersity, S-106 91 Stockholm, Sweden
stefan.oscarson@ucd.ie
ReceiVed May 9, 2008
NIS/AgOTf-promoted glycosylations with ethyl 2,3-N,O-carbonyl-2-deoxy-1-thio-ꢀ-D-glucopyranoside
donors can be performed with either R- or ꢀ-selectivity by tuning the reaction conditions. Small amounts
of AgOTf (0.1 equiv) and short reaction times give ꢀ-selectivity, whereas 0.4 equiv of AgOTf and
prolonged reaction times afford R-linked products. NMR-monitored glycosylation and anomerization
experiments show initial formation of exclusively the ꢀ-linkage, which anomerizes, through an
intramolecular mechanism involving an endocyclic C-O bond cleavage, to the R-linkage.
Introduction
and R/ꢀ-mixtures were produced with acceptors of intermediate
reactivity, and unreactive acceptors gave mainly R-glycosides.7
Recently, Ito and co-workers used N-benzylated thiophenyl
donors and phenylsulfenyl triflate or N-(phenylthio)-ꢀ-capro-
lactam-Tf2O as promoter, to obtain disaccharides with high
R-selectivity.8 We tried the thioethyl N-acetylated donor em-
ploying NIS/AgOTf as promoter system and found that the
stereochemical outcome of the reaction was highly dependent
on the amount of AgOTf used; a catalytic amount gave
ꢀ-selectivity, whereas the use of 0.4 molar equiv and prolonged
reaction time provided R-selectivity.9 We suggested that these
results were due to an efficient anomerization of the initially
formed ꢀ-glycoside when more acidic conditions were used.
During the preparation and revision of this paper, Geng et al.
published results on glycosylations using a preactivation protocol
with similar outcome; that is, the presence of a base gave the
ꢀ-product, whereas more acidic conditions (no base present)
gave the R-linked product.10,11 We herein report a more detailed
investigation of our donor-promoter system and its reaction
mechanism.
Synthesis of 2-acetamido-2-deoxyglycosides is still a chal-
lenge, especially, as with other glycosides, the stereoselective
synthesis of 1,2-cis-glycosides.1,2 In this context, 2N,3O-
oxazolidinone derivatives of 2-amino-2-deoxyglycopyranosides
have aroused a lot of interest recently, both as glycosyl donors
and glycosyl acceptors.3 Thus, Crich and Vinod advocated them
as good 4-OH acceptors, avoiding the low reactivity of the
corresponding GlcNAc acceptors.4,5 Kerns and co-workers
investigated their properties as glycosyl donors. Initially, they
employed a non-N-acylated thiophenyl donor using phenyl-
sulfenyl triflate as promoter to get high yields of disaccharides
and with excellent R-selectivity.6 With the N-acetylated tolyl
thioglycoside donor and BSP-Tf2O as promoter, they reported
a correlation between the R/ꢀ-selectivity and the reactivity of
the acceptor. ꢀ-Selectivity was obtained with reactive acceptors,
† Department of Organic Chemistry.
‡ Division of Structural Chemistry.
§ Present address: University of Bangor, The School of Chemistry, Alun
Roberts Building, Deiniol Road, Bangor, Gwynedd, LL57 2UW, UK.
¶ Present address: Centre for Synthesis and Chemical Biology, University
College Dublin, Belfield, Dublin 4, Ireland.
(1) Banoub, J.; Boullanger, P.; Lafont, D. Chem. ReV. 1992, 92, 1167–1195.
(2) Bongat, A. F. G.; Demchenko, A. V. Carbohydr. Res. 2007, 342, 374.
(3) Litjens, R. E. J. N.; van den Bos, L. J.; Codee, J. D.C.; Overkleeft, H. S.;
van der Marel, G. A. Carbohydr. Res. 2007, 342, 419.
(7) Wei, P.; Kerns, R. J. J. Org. Chem. 2005, 70, 4195.
(8) Manabe, S.; Ishii, K.; Ito, Y. J. Am. Chem. Soc. 2006, 128, 10666.
(9) Boysen, M.; Gemma, E.; Lahmann, M.; Oscarson, S. Chem. Commun.
2005, 3044.
(4) Crich, D.; Vinod, A. U. Org. Lett. 2003, 5, 1297.
(5) Crich, D.; Vinod, A. U. J. Org. Chem. 2005, 70, 1291.
(6) Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001, 123, 9461.
(10) Geng, Y. Q.; Zhang, L. H.; Ye, X. S. Chem. Commun. 2008, 5, 597.
(11) Geng, Y. Q.; Zhang, L. H.; Ye, X. S. Tetrahedron 2008, 64, 4949.
10.1021/jo800971s CCC: $40.75
Published on Web 08/20/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7181–7188 7181

Olsson et al.
SCHEME 1. Synthesis of Glycosyl Donors
equiv of AgOTf was added (entries Vii and Viii). However, with
this donor, also Method A afforded only the R-disaccharides,
but in slightly lower yields.
With some donors (compare entries i and xii), glycosylations
using Method A conditions and donor 4 resulted in an R/ꢀ
mixture. Considering the mechanistic suggestion, this was
thought to be due to unwanted anomerization of the initially
formed ꢀ-product. A solution to this problem should be to use
a promoter that allows buffering with a base to completely
prevent anomerization. Therefore, DMTST was tried as pro-
moter in the presence of DTBMP and was found to give
complete ꢀ-selectivity and good to excellent yields (entries iii,
Vi, xi, and xiV) with all acceptors. The low yield with acceptor
9 (entry iii) was due to substantial decomposition of the donor
not experienced in glycosylations with other acceptors. If
DMTST was used without the addition of base, an anomerization
of the originally obtained ꢀ-glycoside disaccharide was found;
however, this anomerization was much slower and less efficient
than with the NIS/AgOTf promoter system.
Mechanistic Studies. As mentioned, to explain the stereo-
chemical outcome of the glycosylations using the N-acetylated
donors, we anticipated an initial formation of the ꢀ-saccharide
followed by a subsequent anomerization, aided by the presence
of the oxazolidinone group, to the R-glycoside, which was most
efficient under more acidic conditions. To verify this assumption,
the glycosylation between donor 4 and acceptor 7, using 0.1
molar equiv of AgOTf, was performed in the NMR tube (Figure
1). The relative amounts of R- and ꢀ-products at various times
were estimated by integration over specific signals in the proton
spectra (see Experimental Section). As predicted, the ꢀ-glycoside
9 was formed exclusively in the beginning, still after 20 min
only the ꢀ-disaccharide could be detected. However, even with
this small amount of AgOTf, the anomerization process was
found to take place, and within 4 h, 9 was converted completely
to the R-glycoside 10. It is known that the N-acetyloxazolidinone
group facilitates anomerization,5,8,9 and, as expected, the methyl
glycoside did not anomerize under these conditions.
Results and Discussion
Synthesis of Glycosyl Donors. In our earlier communication,
the 4,6-di-O-benzylated-protected oxazolidinone donor was
used.9 Shorter pathways to this donor as well as to other donors
with different 4,6-O-protecting groups were investigated (Scheme
1). Ethyl 2-amino-2-deoxy-1-thio-ꢀ-D-glucopyranoside12 (1) was
treated with triphosgene13 to regioselectively give the 2,3-cyclic
carbamate 2 in high yield (89%). Unfortunately, attempts to
selectively O-benzylate this compound were not successful, only
the 2N,4,6-di-O-tribenzylated compound was isolated. However,
selective O-acetylation was achieved using Ac2O and pyridine
to give compound 3 (84%), which could then be N-acetylated
with AcCl and DIPEA (f 4, 94%) or N-benzylated using BnBr/
NaH/DMF (f 5, 72%). Treatment of compound 2 with
benzaldehyde dimethylacetal under acidic conditions afforded
the 4,6-O-benzylidenated derivative (53%), which was N-
acetylated using AcCl and DIPEA to give 6 (53%).
Glycosylation Results. The new compounds 4-6 were
investigated for their donor properties using various acceptors,
galactopyranosides 714 and 8,15 mannopyranoside 15,16 rham-
nopyranoside 16,17 and the glycosylation conditions (Method
A or B) developed earlier (Table 1). The 4,6-O-benzylidene
derivative 6 was found to be inert to activation by NIS/AgOTf,
while the 4,6-O-acetylated derivative 4 gave very similar results
to the corresponding 4,6-O-benzylated donor tried earlier.9 Once
again, the stereochemical outcome could be controlled by the
amount of AgOTf used in the glycosylation and the reaction
time; 0.1 equiv of AgOTf and reaction time of around 10 min
gave the ꢀ-linked product, whereas 0.4 equiv and around 40
min produced the R-disaccharide with excellent stereoselectivity
(entries i, ii, iV, V, ix, x, xii, and xiii, Table 1). The N-benzylated
donor 5, too, gave exclusively the R-linked products when 0.4
The anomerization reaction was also studied in the NMR tube
(Figure 2). Compound 9 (>95% ꢀ) was treated with a catalytic
amount of AgOTf. Once more an efficient anomerization was
observed giving the R-linked disaccharide 10 almost exclusively
and efficiently (>90% yield) after 4 h.
This selective and high-yielding anomerization, with no or
negligible hydrolysis, suggested to us that the mechanism is
probably via an activation of the ring oxygen and a consecutive
endocyclic C-O bond cleavage in preference over an exocyclic
cleavage.18 Since the endocyclic mechanism entails an intramo-
lecular pathway (the “glycosidic” bond is not cleaved see
Scheme 4 below), that would explain the high yields observed.
To try to confirm this mechanism, the anomerization reaction
was performed in the presence of an excess of methanol (Figure
3), which in the case of an exocyclic intermolecular pathway
would be expected to give substantial amount of methanolysis
product. However, no such monosaccharide products were
detected; only the R-linked disaccharide was again formed and
once more in high yield (80%), which strongly corroborates
the endocyclic pathway. Attempts to trap the ring-opened
intermediate by hydride reducing reagents were performed but
were unsuccessful.
(12) Buskas, T.; Garegg, P. J.; Konradsson, P.; Maloisel, J.-L. Tetrahedron:
Asymmetry 1994, 5, 2187.
(13) Ichikawa, Y.; Matsukawa, Y.; Nishiyama, T.; Isobe, M. Eur. J. Org.
Chem. 2004, 586.
(14) Katsunori Kohata, K.; Abbas, S. A.; Matta, K. L. Carbohydr. Res. 1984,
132, 127.
(15) Ek, M.; Garegg, P. J.; Hultberg, H.; Oscarson, S. J. Carbohydr. Chem.
Oligosaccharide Synthesis. To further investigate the scope
of this type of donors, the synthesis of an oligosaccharide
1983, 2, 305.
(16) Sondheimer, S. J.; Eby, R.; Schuerch, C. Carbohydr. Res. 1978, 60,
187.
(17) van Summeren, R. P.; Feringa, B. L.; Minnaard, A. J. Org. Biomol.
Chem. 2005, 3, 2524.
(18) Lindberg, B. Acta Chem. Scand. 1949, 3, 1153.
7182 J. Org. Chem. Vol. 73, No. 18, 2008

2-N-Acetyl-2N,3O-oxazolidinone-Protected Glucosamine Donors
TABLE 1. Glycosylation Reactions
Method A: Acceptor (1 equiv), donor (1.2-1.5 equiv), CH2Cl2, 4 Å molecular sieves, NIS (2 equiv), AgOTf (0.1 equiv.), rt, 10-20 min. Method B:
Acceptor (1 equiv), donor (1.2-1.5 equiv), CH2Cl2, 4 Å molecular sieves, NIS (2 equiv), AgOTf (0.4 equiv), rt, 25-45 min. Method C: Acceptor (1
equiv), donor (1.2-1.5 equiv), CH2Cl2, 4 Å molecular sieves, DMTST (2 equiv), DTBMP (2.7 equiv), 0 to 20 °C, 30 min.
J. Org. Chem. Vol. 73, No. 18, 2008 7183

Olsson et al.
SCHEME 2. Synthesis of Trisaccharide 25
Glycosylation of acceptor 22 (obtained by regioselective chlo-
roacetylation of compound 2119) using Method B (Table 1)
condition and 1.4 equiv of donor 4 afforded the expected
R-linked disaccharide 23 in 46% yield, a yield that was improved
to 82% when 1.8 donor equiv was used. Treatment with thiourea
removed the chloroacetyl group to afford the 6-OH acceptor
24 (84%). The subsequent ꢀ-glycosylation of acceptor 24 with
donor 4 was tried using both Method A and Method C
conditions. DMTST/DTBMP was found to be the best promoter
system, affording target trisaccharide 25 in 77% yield.
FIGURE 1. Relative amounts of ꢀ- and R-product disaccharides (9
and 10) versus time in NIS/AgOTf (0.1 equiv)-promoted glycosylation
between donor 4 and acceptor 7 as estimated by NMR.
In the synthesis of a tetrasaccharide corresponding to a
Neisseria meningitidis inner core LPS structure,20 problems were
encountered during the introduction of an R-linked GlcNAc
moiety to the acceptor 2621 (Scheme 3). 2-Azido-2-deoxyglu-
copyranose donors gave high yields but low stereoselectivity
(at the best R/ꢀ 1.5:1) in the couplings. Therefore, donor 4 was
tried using the conditions (Method B) that were shown to give
R-selectivity. Most satisfactorily, this approach gave exclusively
the R-linked [H-1′′′ δ 5.81 (d, J ) 2.5 Hz)] tetrasaccharide 27
in 92% yield, proving the application of the methodology also
to complex oligosaccharide synthesis.
FIGURE 2. Relative amounts of ꢀ- and R-disaccharides (9 and 10)
versus time in AgOTf (0.1 equiv)-promoted anomerization of compound
9 as estimated by NMR.
Discussion and Conclusions
We have found that in glycosylation reactions with N-
acetylated 2N,3O-oxazolidinone thioglycoside donors using NIS/
AgOTf as promoter the stereochemical outcome of glycosylation
reactions is determined by the reaction conditions used.
Exclusively the ꢀ- or the R-glycoside product can be obtained
from the same donor by tuning the reaction conditions. NMR-
monitored glycosylation reactions show that the ꢀ-glycoside is
initially formed and can be isolated if short reaction time and
low acidity conditions are used. If longer time and/or more acidic
conditions are employed, an efficient anomerization to give
exclusively the corresponding R-glycoside takes place. These
results and selectivities have also been found to be valid in more
complex cases, such as the synthesis of tri- and tetrasaccharides.
NMR-monitored anomerization experiments strongly suggest
that the anomerization is an intramolecular reaction proceeding
via an endocyclic C-O bond cleavage (Scheme 4). Both the
N-acetyl and the oxazolidinone group as well as AgOTf were
found to be important for an effective anomerization. The
rationale behind the initial formation of the ꢀ-product has not
been studied. However, the crystal structure of donor 4 has been
elucidated (Figure 4) showing the N-acetyl group on the ꢀ-side
of the molecule in a position where it can not act as a
FIGURE 3. Relative amount of ꢀ- and R-disaccharides (9 and 10)
versus time in AgOTf (excess)-promoted anomerization of compound
9 in the presence of MeOH (8 equiv) as estimated by NMR.
containing both R- and ꢀ-linked glucosamine residues was
attempted (Scheme 2). As the target structure, an R-(1f2)-
analogue of the branched trisaccharide ꢀ-D-GlcNAcp-(1f2)-
[ꢀ-D-GlcNAcp-(1f6)]-R-D-Manp found in the complex form
of N-glycans was selected. In line with the suggested mecha-
nism, the R-linked GlcNAc moiety had to be introduced first.
(19) Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org. Chem.
1996, 61, 3897.
(20) Raetz, C. R. H.; Whitfield, C. Annu. ReV. Biochem. 2002, 71, 635.
(21) Segerstedt, E.; Mannerstedt, K.; Johansson, M.; Oscarson, S. J. Car-
bohydr. Chem. 2004, 23, 443.
7184 J. Org. Chem. Vol. 73, No. 18, 2008

2-N-Acetyl-2N,3O-oxazolidinone-Protected Glucosamine Donors
SCHEME 3. Synthesis of Tetrasaccharide 27
SCHEME 4. Proposed Mechanism for the Anomerization Reaction of Compound 9
J ) 9.6 Hz); EI-HRMS calcd for C9H15NO5S [M + Na]+ 272.0569,
found 272.0585.
participating group, findings that are corroborated by molecular
modeling performed by Wei and Kerns.7
Ethyl 4,6-Di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-1-thio-ꢀ-D-glu-
copyranoside (3). Compound 2 (0.484 g, 1.94 mmol) was dissolved
in pyridine/Ac2O (3:2, 10 mL) at 0 °C. After 2 h, the mixture was
coevaporated with toluene (3 × 15 mL). FC (toluene/EtOAc 2:1)
afforded 3 (0.543 g, 1.63 mmol, 84%) as a white foam: Rf 0.53
(toluene/EtOAc 1:1); [R]D -29 (c 1.0, CHCl3); 13C NMR (75.4
MHz, CDCl3) δ 15.4, 20.7, 20.8, 25.0, 59.2, 62.3, 67.6, 77.4, 82.0,
If the R-selective properties of the N-benzylated donor 5 are
due to the same mechanism as for donor 4, but with an even
faster anomerization rate, or if in this case the R-linked
disaccharide is the initial product has not yet been established.
1
83.2, 158.5, 169.3, 170.7; H NMR (300 MHz, CDCl3) δ 1.32 (t,
3H, J ) 7.5 Hz), 2.08 (s, 3H), 2.11 (s, 3H), 2.73 (m, 2H), 3.58
(ddd, 1H, J12 ) 9.6, J23 ) 9.6, J ) 1.2 Hz), 3.74 (ddd, 1H, J )
9.0, J ) 2.7, J ) 5.1 Hz), 4.16 - 4.27 (m, 3H), 4.62 (d, 1H, J )
9.6 Hz), 5.30 (dd, 1H, J34 ) 10.2, J ) 9.0, Hz), 5.37 (br s, 1H);
EI-HRMS calcd for C13H19NO7S [M + Na]+ 356.0780, found
356.0766.
Ethyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
1-thio-ꢀ-D-glucopyranoside (4). Compound 3 (0.126 g, 0.378 mmol)
was dissolved in dry CH2Cl2 (3 mL), and DIPEA (0.33 mL, 1.89
mmol) and AcCl (0.134 mL, 1.89 mmol) were added at 0 °C. After
20 min, the mixture was diluted with CH2Cl2 (12 mL), washed
with NaHCO3 (sat. aq, 15 mL), 1 M HCl (15 mL), and subjected
to normal workup. FC (toluene/EtOAc 6:1f 3:1) followed by
crystallization from Et2O/pentane gave 4 (0.134 g, 0.357 mmol,
94%) as white crystals: Rf 0.67 (toluene/EtOAc 1:1); mp 52-53
°C; [R]D -23 (c 1.0, CHCl3); 13C NMR (75.4 MHz, CDCl3) δ 14.3,
20.7, 20.8, 24.8, 25.6, 60.1, 62.3, 67.8, 77.4, 79.5, 85.2, 153.5,
169.2, 170.6, 172.7; 1H NMR (300 MHz, CDCl3) δ 1.25 (t, 3H, J
) 7.5 Hz), 2.06 (s, 3H), 2.11 (s, 3H), 2.50 (s, 3H), 2.64 (m, 2H),
3.76 (m, 1H), 4.06 (dd, 1H, J ) 8.4, J ) 11.1 Hz), 4.20 - 4.27
(m, 3H), 4. 76 (d, 1H, J ) 8.4 Hz), 5.28 (dd, 1H, J ) 10.2, J )
9.0, Hz); EI-HRMS calcd for C15H21NO8S [M + Na]+ 398.0886,
found 398.0867.
Ethyl 4,6-Di-O-acetyl-2-N-benzyl-2,3-N,O-carbonyl-2-deoxy-1-
thio-ꢀ-D-glucopyranoside (5). Compound 3 (0.086 g, 0.258 mmol)
was dissolved in dry DMF (2 mL), and benzyl bromide (0.046 mL,
0.387 mmol) was added. This solution was added dropwise to a
cooled (0 °C) slurry of NaH (0.008 g, 0.335 mmol) in DMF (1
mL). After 30 min, MeOH (0.5 mL) was added and the mixture
was diluted with H20 (40 mL) and toluene (50 mL). The organic
phase was separated and subjected to normal workup, followed by
FIGURE 4. X-ray structure of compound 4.
Experimental Section
Ethyl-2,3-N,O-Carbonyl-2-deoxy-1-thio-ꢀ-D-glucopyranoside (2).
Ethyl 2-amino-2-deoxy-1-thio-ꢀ-D-glycopyranoside (0.487 g, 2.18
mmol) was dissolved in MeCN (20 mL), and NaHCO3 (sat. aq, 10
mL) was added. The mixture was cooled to 0 °C, and triphosgene
(0.259 g, 0.872 mmol) was added to the vigorously stirred mixture.
After 30 min, EtOAc (30 mL) containing ethylenediamine (0.408
mL, 6.107 mmol) was added and the stirring was continued for 5
min. Normal workup gave 2 (0.484 g,1.94 mmol, 89%) as an
analytically pure white solid: Rf 0.60 (CHCl3/CH3OH 5:1); [R]D
-54 (c 1.0, CH3OH); 13C NMR (75.4 MHz, CD3OD) δ 15.5, 25.0,
60.6, 62.0, 68.5, 83.7, 83.9, 86.3, 162.2; 1H NMR (300 MHz,
CD3OD) δ 1.30 (t, 3H, J ) 7.5 Hz), 2.77 (m, 2H), 3.41 (m, 1H),
3.42 (dd, 1H, J ) 9.6, 11.1 Hz), 3.74 (dd, 1H, J ) 5.1, 12.0 Hz),
3.84-3.90 (m, 2H), 4.12 (dd, 1H, J ) 10.2, 11.1 Hz), 4.74 (d, 1H,
J. Org. Chem. Vol. 73, No. 18, 2008 7185

Olsson et al.
FC (toluene/EtOAc 6:1) to give 5 (0.079 g, 0.187 mmol, 72%): Rf
0.53 (toluene/EtOAc 2:1); [R]D -70 (c 1.0, CHCl3); 13C NMR (75.4
MHz, CDCl3) δ 14.8, 20.6, 20.7, 25.2, 47.3, 60.0, 62.3, 67.5, 77.2,
80.0, 83.8, 127.8, 128.4 (2C), 128.7 (2C), 135.7, 158.6, 169.2,
127.6 (2C), 128.0, 128.1 (2C), 128.2 (2C), 128.5 (2C), 128.6 (2C),
128.8 (2C), 138.0, 139.0, 139.3, 153.6, 169.5, 170.5, 170.6; H
1
NMR (300 MHz, CDCl3) δ 1.98 (s, 3H), 2.12 (s, 3H), 2.28 (s,
3H), 3.51 (s, 3H), 3.63-3.59 (m, 3H), 3.94-3.80 (m, 5H), 4.03
(dd, 1H, J ) 9.9, 12.3 Hz), 4.12 (dd, 1H, J ) 6.6, 12.3 Hz), 4.26
(d, 1H, J ) 6.9 Hz), 4.34 (dd, 1H, J ) 3.3, 12.0 Hz), 4.42 (benzylic
d, 1H, Jgem ) 12.0 Hz), 4.47 (benzylic d, 1H, Jgem ) 10.8), 4.51
1
170.6; H NMR (300 MHz, CDCl3) δ 1.19 (t, 3H, J ) 7.5 Hz),
2.02 (s, 3H), 2.08 (s, 3H), 2.53 (m, 2H), 3.40 (dd, 1H, J ) 9.6, J
) 11.1 Hz), 3.72 (m, 1H), 4.10-4.22 (m, 3H), 4.58 (benzylic d,
1H, Jgem ) 16.3 Hz), 4.63 (d, 1H, J ) 9.6 Hz), 4.73 (benzylic d,
1H, Jgem ) 16.3 Hz), 5.21 (dd, 1H, J ) 10.2, J ) 9.3 Hz), 7.27 -
7.34 (m, 5H, Ar-H); EI-HRMS calcd for C20H25NO7S: [M + Na]+
446.1244, found 446.1234.
(benzylic d, 1H, Jgem ) 11.4 Hz), 4.62 (benzylic d, 1H, Jgem
)
11.4 Hz), 4.99 (benzylic d, 1H, Jgem ) 11.4 Hz), 5.01 (benzylic d,
1H, Jgem ) 11.4 Hz), 5.12 (dd, 1H, J ) 6.9, 9.9 Hz), 5.35 (d, 1H,
J ) 6.9 Hz), 7.23-7.42 (m, 15H); EI-HRMS calcd for C41H47NO14
[M + Na]+ 800.2894, found 800.2906.
Ethyl 2-Acetamido-4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-
1-thio-ꢀ-D-glucopyranoside (6). PhCH(OMe)2 (0.31 mL, 2.046
mmol) and CSA (0.024 g, 0.102 mmol) were added to a solution
of compound 2 (0.255 g, 1.023 mmol) in DMF (10 mL). After
stirring at 50 °C for 18 h, the solution was diluted with EtOAc (50
mL), washed with NaHCO3 (sat. aq, 80 mL), and subjected to
normal workup. FC (toluene/EtOAc 3:1) gave the 4,6-O-ben-
zylidene derivative (0.183 g, 0.542 mmol, 53%) as a white solid.
This derivative (0.176 g, 0.521 mmol) was dissolved in dry CH2Cl2
(5 mL), and DIPEA (0.27 mL, 1.57 mmol) and AcCl (0.111 mL,
1.57 mmol) were added at 0 °C. After 30 min, the mixture was
diluted with CH2Cl2 (15 mL), washed with NaHCO3 (sat. aq, 20
mL), 1 M HCl (20 mL), and subjected to normal workup. FC
(toluene/EtOAc 6:1) followed by crystallization from EtOAc/light
petroleum (65-75) gave 5 (0.183 g, 0.542 mmol, 53%) as a white
solid: Rf 0.78 (toluene/EtOAc 2:1); mp 194-196 °C; [R]D -44 (c
1.0, CHCl3); 13C NMR (75.4 MHz, CDCl3) δ 14.3, 25.0, 25.7, 61.1,
68.4, 73.3, 78.6, 78.9, 86.2, 101.6, 126.2 (2C), 128.5 (2C), 129.5,
136.4, 153.8, 173.3; 1H NMR (300 MHz, CDCl3) δ 1.27 (t, 3H, J
) 7.5 Hz), 2.54 (s, 3H), 2.67 (m, 2H), 3.63 (ddd, 1H, J ) 4.5, 8.7,
9.9 Hz), 3.94 (dd, 1H, J ) 10.2, 10.2 Hz), 4.03-4.10 (m, 2H),
4.33-4.42 (m, 2H), 4.83 (d, 1H, J ) 8.7 Hz), 5.62 (s, 1H),
7.36-7.50 (m, 5H, Ar-H); EI-HRMS calcd for C18H21NO6S [M
+ Na]+ 402.0987, found 402.1000.
General Methods for the Glycosylation Reactions. Method
A: The glycosyl acceptor 7 or 8 (approximately 0.10 mmol, 1 equiv)
and a slight excess of the glycosyl donor 4 or 5 (1.2-1.5 equiv)
were dissolved in dry CH2Cl2 (1 mL); 4 Å molecular sieves were
added, and the mixture was stirred for 10-15 min under an argon
atmosphere. NIS (2.0 equiv) and AgOTf (approximately 0.1 equiv)
were added, and the mixture was stirred for an additional 10-20
min. Et3N was added, and the mixture was applied to a silica gel
column. FC (toluene f toluene/EtOAc 19:1f 9:1 f 6:1f 3:1)
gave the desired disaccharide.
Method B: The glycosyl acceptor 7 or 8 (approximately 0.10
mmol, 1 equiv) and a slight excess of the glycosyl donor 4 or 5
(1.2-1.5 equiv) were dissolved in dry CH2Cl2 (1 mL); 4 Å
molecular sieves were added, and the mixture was stirred for 5-15
min under an argon atmosphere. NIS (2.0 equiv) and AgOTf (0.4
equiv) were added, and the mixture was stirred for an additional
25-45 min and then applied to a silica gel column. FC (toluene f
toluene/EtOAc 19:1f 9:1 f 6:1f 3:1) gave the desired disaccharide.
Method C: The glycosyl acceptor 15 or 16 (approximately 0.05
mmol, 1 equiv), a slight excess of the glycosyl donor 4 (1.5 equiv),
and DTBMP (2.7 equiv) were dissolved in dry CH2Cl2 (1 mL); 4
Å molecular sieves were added, and the mixture was stirred for 20
min under an argon atmosphere. The mixture was cooled to 0 °C,
and DMTST (2.0 equiv) was added. The reaction was brought to
20 °C over 30 min and then quenched with Et3N. The mixture was
filtered through Celite, the solvent evaporated, and the residue
applied to a silica gel column. FC (toluene/EtOAc 9:1 f 6:1 f
3:1) gave the desired disaccharide.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
r-D-glucopyranosyl-(1f3)-2,4,6-tri-O-benzyl-ꢀ-D-galactopyrano-
side (10). Yield 82%; Rf 0.79 (toluene/EtOAc 1:1); [R]D +61 (c
2.0, CHCl3); 13C NMR (75.4 MHz, CDCl3) δ 20.8, 20.8, 23.3, 57.3,
60.1, 61.1, 68.0, 68.3, 69.7, 73.3, 73.7, 73.8, 73.9, 74.6, 75.2, 76.8,
77.7, 93.0, 105.5, 127.0 (2C), 127.6, 128.0, 128.0, 128.1 (2C), 128.3
(2C), 128.5 (2C), 128.5 (2C), 128.6 (2C), 137.8, 138.3, 138.9, 152.6,
1
169.2, 170.6, 172.2; H NMR (300 MHz, CDCl3) δ 2.03 (s, 3H),
2.04 (s, 3H), 2.05 (s, 3H), 3.55 (s, 3H), 3.60 (m, 3H), 3.78-3.91
(m, 5H), 3.94 (dd, 1H, J ) 2.4, 12.6 Hz), 4.23-4.30 (m, 2H), 4.42
(benzylic d, 1H, Jgem ) 11.7 Hz), 4.58-4.48 (m, 4H), 4.65 (benzylic
d, 1H, Jgem ) 11.1 Hz), 4.96 (benzylic d, 1H, Jgem ) 10.8 Hz),
5.22 (t, 1H, J ) 9.9 Hz), 5.87 (d, 1H, J ) 2.7 Hz), 7.23-7.39 (m,
15H); EI-HRMS calcd for C41H47NO14 [M + Na]+ 800.2894, found
800.2853.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
ꢀ-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-ꢀ-D-galactopyrano-
side (11). Yield 76% (Method A) and 64% (Method C); Rf 0.72
(toluene/EtOAc 1:1); [R]D -20 (c 0.8, CHCl3); 13C NMR (75.4
MHz, CDCl3) δ 20.8, 20.9, 24.7, 57.1, 60.8, 63.7, 67.7, 69.7, 73.1,
73.4, 73.8, 74.5, 75.2, 75.4, 77.0, 79.6, 82.1, 100.4, 105.1,
127.6-128.5 (15C), 138.6, 138.7, 139.0, 153.3, 169.6, 170.4, 170.6;
1H NMR (300 MHz, CDCl3) δ 2.02 (s, 3H), 2.13 (s, 3H), 2.47 (s,
3H), 3.51 (s, 3H), 3.58 (dd, 1H, J ) 2.7, 9.9 Hz), 3.64-3.90 (m,
5H), 3.94-4.01 (m, 2H), 4.12-4.25 (m, 2H), 4.29 (d, 1H, J ) 7.2
Hz), 4.42 (dd, 1H, J ) 4.8, 11.7 Hz), 4.63 (benzylic d, 1H, Jgem
)
11.7 Hz), 4.75-4.78 (m, 3H), 4.89 (benzylic d, 1H, Jgem ) 11.1
Hz), 4.98 (benzylic d, 1H, Jgem ) 11.7 Hz), 5.11 (dd, 1H, J ) 4.2,
9.6 Hz), 5.14 (d, 1H, J ) 6.9 Hz), 7.24-7.38 (m, 15H); EI-HRMS
calcd for C41H47NO14 [M + Na]+ 800.2894, found 800.2853.
Methyl 2-Acetamido-4,6-O-acetyl-2,3-N,O-carbonyl-2-deoxy-r-
D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-ꢀ-D-galactopyrano-
side (12). Yield 68%; Rf 0.83 (toluene/EtOAc 1:1); [R]D +40 (c
0.4, CHCl3); 13C NMR (75.4 MHz, CDCl3) δ 20.7, 20.8, 23.9, 57.1,
60.1, 61.6, 68.0, 70.1, 73.0, 73.5, 73.9, 74.4, 74.4, 75.3, 79.6, 82.1,
95.3, 105.1, 127.7, 127.8 (2C), 127.9, 128.0, 128.2 (2C), 128.4 (4C),
128.5 (2C), 128.6 (2C), 138.3, 138.5, 138.8, 152.8, 169.2, 170.7,
171.1 (Note: one 13C signal overlaps with solvent peaks); 1H NMR
(300 MHz, CDCl3) δ 2.06 (s, 3H), 2.11 (s, 3H), 2.46 (s, 3H),
3.44-3.53 (m, 3H), 3.54 (s, 3H), 3.67 (d, 1H, J ) 2.7 Hz),
3.77-3.95 (m, 4H), 4.13 (dd, 1H, J ) 2.1, 12.3 Hz), 4.21-4.28
(m, 2 H), 4.55-4.62 (m, 2H), 4.73 (benzylic d, 1H, Jgem ) 12.0
Hz), 4.76 (benzylic d, 1H, Jgem ) 10.8 Hz), 4.82 (benzylic d, 1H,
Jgem ) 12.0 Hz), 4.91 (benzylic d, 1H, Jgem ) 10.5 Hz), 4.94
(benzylic d, 1H, Jgem ) 11.1 Hz), 5.29 (t, 1H, J ) 9.9 Hz), 5.64
(d, 1H, J ) 2.7 Hz), 7.28-7.38 (m, 15H); EI-HRMS calcd for
C41H47NO14 [M + Na]+ 800.2894, found 800.2853.
Methyl 4,6-Di-O-acetyl-2-N-benzyl-2,3-N,O-carbonyl-2-deoxy-
r-D-glucopyranosyl-(1f3)-2,4,6-tri-O-benzyl-ꢀ-D-galactopyrano-
side (13). Yield 65%; Rf 0.60 (toluene/EtOAc 2:1); [R]D +28 (c
1.0, CHCl3); 13C NMR (75.4 MHz, CDCl3) δ 20.8 (2C), 48.3, 57.3,
60.7, 61.6, 68.6, 68.4, 70.6, 73.1, 73.6, 73.8, 74.3, 74.6, 75.2, 77.9,
78.8, 93.4, 105.3, 127.4 (2C), 127.9 (2C), 128.1 (2C), 128.1, 128.2
(2C), 128.5, 128.5 (3C), 128.7 (2C), 128.8 (2C), 129.3 (2C), 134.9,
137.9, 138.1, 138.5, 158.6, 169.3, 170.6; 1H NMR (300 MHz,
CDCl3) δ 1.98 (s, 3H), 2.02 (s, 3H), 3.30 (dd, 1H, J ) 2.7, 11.7
Hz), 3.37 (dd, 1H, J ) 3.0, 9.6 Hz), 3.53 (s, 3H), 3.55 (m, 1H),
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
ꢀ-D-glucopyranosyl-(1f3)-2,4,6-tri-O-benzyl-ꢀ-D-galactopyrano-
side (9). Yield 67% (Method A) and 33% (Method C); Rf 0.79
(toluene/EtOAc 1:1); [R]D -2 (c 1.0, CHCl3); 13C NMR (75.4 MHz,
CDCl3) δ 20.7, 20.8, 24.7, 57.0, 60.6, 63.0, 68.8 (2C), 73.7 (2C),
74.5, 74.7, 75.6, 75.8, 75.9, 79.8, 80.1, 102.2, 105.2, 127.0 (2C),
7186 J. Org. Chem. Vol. 73, No. 18, 2008

2-N-Acetyl-2N,3O-oxazolidinone-Protected Glucosamine Donors
3.66-3.69 (m, 2H), 3.73 (dd, 1H, J ) 7.2, 9.6 Hz), 3.79 (d, 1H, J
) 2.1 Hz), 3.89-3.91 (m, 2H), 4.02 (benzylic d, 1H, Jgem ) 15.0
Hz), 4.08 (m, 1H), 4.22 (d, 1H, J ) 7.2 Hz), 4.37-4.51 (m, 2H),
4.49 (benzylic d, 1H, Jgem ) 11.4 Hz), 4.56 (benzylic d, 1H, Jgem
) 11.7 Hz), 4.62 (benzylic d, 1H, Jgem ) 11.4 Hz), 4.65 (benzylic
d, 1H, Jgem ) 10.5 Hz), 4.79 (benzylic d, 1H, Jgem ) 11.4 Hz),
4.91 (benzylic d, 1H, Jgem ) 10.5 Hz), 5.13 (t, 1H, J ) 9.9 Hz),
5.26 (d, 1H, J ) 2.7 Hz), 7.17-7.38 (m, 20H, Ar-H); EI-HRMS
calcd for C46H51NO13 [M + K]+ 864.2992, found 864.2949.
Methyl 4,6-Di-O-acetyl-2-N-benzyl-2,3-N,O-carbonyl-2-deoxy-
r-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-ꢀ-D-galactopyrano-
side (14). Yield 68%; Rf 0.56 (toluene/EtOAc 2:1); [R]D +18 (c
1.0, CHCl3); 13C NMR (75.4 MHz, CDCl3) δ 20.7, 20.8, 48.7, 57.1,
61.2, 61.6, 68.4 (2C), 70.5, 73.3, 73.7, 73.8, 74.0, 74.2, 75.3, 79.7,
82.0, 95.0, 105.1, 127.8, 127.9 (2C), 128.0, 128.0, 128.2 (2C), 128.4
(3C), 128.5 (2C), 128.5 (2C), 128.6 (2C), 128.9 (2C), 128.9 (2C),
135.2, 138.3, 138.5, 138.8, 158.4, 169.3, 170.6; 1H NMR (300 MHz,
CDCl3) δ 2.01 (s, 3H), 2.08 (s, 3H), 3.29-3.35 (m, 2H), 3.48-3.56
(m, 2H), 3.54 (s, 3H), 3.64 (dd, 1H, J ) 7.5, 9.9 Hz), 3.78 (dd,
1H, J ) 7.5, 9.6 Hz), 3.84 (m, 1H), 4.04 (dd, 1H, J ) 3.5, 12.3
Hz), 4.19 (dd, 1H, J ) 4.5, 12.3 Hz), 4.25 (d, 1H, J ) 7.8 Hz),
4.32 (s, 2H), 4.50 (dd, 1H, J ) 10.2, 12.0 Hz), 4.58 (d, 1H, J )
2.7 Hz), 4.59 (benzylic d, 1H, Jgem ) 12.0 Hz), 4.75 (benzylic d,
1H, Jgem ) 12.0 Hz), 4.76 (benzylic d, 1H, Jgem ) 11.1 Hz), 4.86
) 10.0, 12.0 Hz), 4.33-4.41 (m, 2H), 5.08 (s, 1H), 5.18 (dd, 1H,
J ) 5.0, 10.0 Hz), 5.55 (d, 1H, J ) 7.5 Hz); EI-HRMS calcd for
C23H33NO13 [M + H]+ 532.2030, found 532.2019.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
r-D-glycopyranosyl-(1f4)-2,3-O-isopropylidene-r-L-rhamnopyra-
noside (20). Yield 62%; Rf 0.48 (toluene/EtOAc 2:1); [R]D +96 (c
1.0, CHCl3); 13C NMR (100 MHz, CDCl3) δ 17.5, 20.9, 20.9, 23.9,
26.5, 28.3, 55.1, 60.4, 61.4, 64.4, 68.1, 70.1, 74.2, 76.1, 77.1, 81.3,
96.0, 97.9, 109.6, 152.9, 169.4, 170.9, 171.7; 1H NMR (400 MHz,
CDCl3) δ 1.21 (d, 3H, J ) 6.4 Hz), 1.34 (s, 3H), 1.52 (s, 3H), 2.09
(s, 3H), 2.12 (s, 3H), 2.50 (s, 3H), 3.35 (s, 3H), 3.44 (dd, 1H, J )
6.0, 10.0 Hz), 3.59 (dd, 1H, J ) 6.0, 10.0 Hz), 3.89 (dd, 1H, J )
2.8, 12.0 Hz), 4.07-4.12 (m, 3H), 4.34 (m, 1H), 4.33 (dd, 1H, J )
2.8, 12.0 Hz), 4.65 (dd, 1H, J ) 2.8, 12.0 Hz), 4.84 (s, 1H), 5.37
(dd, 1H, J ) 10.0, 10.0 Hz), 5.83 (d, 1H, J ) 2.8 Hz); EI-HRMS
calcd for C23H33NO13 [M + Na]+ 554.1844, found 554.1838.
Methyl 6-O-Chloroacetyl-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-
r-D-mannopyranoside (22). Compound 2119 (0.612 g, 1.98 mmol)
was dissolved in CH2Cl2/pyridine (14:1, 15 mL), and the solution
was cooled to -70 °C. Chloroacetyl chloride (0.173 mL, 2.18
mmol) was added dropwise, and the mixture was slowly brought
to -20 °C over 90 min and the reaction was then quenched with
MeOH (3 mL). The mixture was diluted with CH2Cl2 (10 mL),
washed with 1 M HCl (50 mL), and subjected to normal workup.
FC (toluene/EtOAc 3:1f 1:1) gave 22 (0.648 g, 1.68 mmol, 85%)
as a white foam: Rf 0.71 (toluene/EtOAc 1:3); [R]D +183 (c 1.0,
CHCl3); 13C NMR (125.6 MHz, 30 °C, CDCl3) δ 17.8, 17.9, 40.9,
48.2, 48.3, 55.2, 63.3, 64.5, 68.4, 68.5, 69.8, 100.2, 100.6, 101.3,
167.4; 1H NMR (500 MHz, 30 °C, CDCl3) δ 1.28 (s, 3H), 1.32 (s,
3H), 3.23 (s, 3H), 3.27 (s, 3H), 3.38 (s, 3H), 3.92-4.10 (m, 6H),
4.33 (dd, 1H, J ) 6.0, 12.0 Hz), 4.52 (d, J ) 12.0 Hz), 4.73 (s,
1H); EI-HRMS calcd for C15H25ClO9 [M + Na]+ 407.1085, found
407.1078.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
r-D-glycopyranosyl-(1f2)-6-O-chloroacetyl-3,4-O-(2,3-dimethoxy-
butane-2,3-diyl)-r-D-mannopyranoside (23). Acceptor 22 (0.126 g,
0.327 mmol) and donor 4 (0.225 g, 0.599 mmol) were dissolved
in dry CH2Cl2 (5 mL) containing crushed 4 Å molecular sieves.
After stirring for 30 min under argon, the mixture was cooled to 0
°C. NIS (0.162 g, 0.719 mmol) and AgOTf (0.042 g, 0.164 mmol)
were added, and the mixture was stirred for an additional 30 min.
The reaction was quenched with Et3N (0.300 mL) and the mixture
filtered through Celite, washed with Na2S2O3 (10% aq, 20 mL),
and subjected to normal workup. FC (toluene/EtOAc 19:1 f 6:1
f 3:1) afforded 23 (0.188 g, 0.269 mmol, 82%): Rf 0.65 (toluene/
EtOAc 1:1); [R]D +115 (c 1.0, CHCl3); 13C NMR (125.6 MHz, 30
°C, CDCl3) δ 17.8, 17.9, 20.8, 20.9, 23.7, 40.8, 48.2, 48.3, 55.3,
60.1, 62.2, 63.1, 64.0, 67.0, 68.6, 68.7, 71.0, 74.1, 77.4, 97.0, 100.2,
100.3, 100.4, 153.1, 167.2, 169.4, 170.6, 170.9; 1H NMR (500 MHz,
30 °C, CDCl3) δ 1.24 (s, 3H), 1.25 (s, 3H), 2.08 (s, 3H), 2.14 (s,
3H), 2.49 (s, 3H), 3.19 (s, 3H), 3.23 (s, 3H), 3.37 (s, 3H), 3.85-4.00
(m, 6H), 4.11 (s, 2H), 4.14 (dd, 1H, J ) 5.0, 12.0 Hz), 4.23 (dd,
1H, J ) 2.0, 12.0 Hz), 4.35 (dd, 1H, J ) 4.5, 12.0 Hz), 4.48 (dd,
1H, J ) 2.0, 12.0 Hz), 4.69 (dd, 1H, J ) 10.5, 10.5 Hz), 4.76 (s,
1H), 5.27 (dd, 1H, J ) 10.0, 10.0 Hz), 5.81 (d, 1H, J ) 2.5 Hz);
EI-HRMS calcd for C28H40ClNO17 [M + Na]+ 720.1874, found
720.1882.
(benzylic d, 1H, Jgem ) 12.0 Hz), 4.92 (benzylic d, 1H, Jgem
)
11.1 Hz), 4.97 (benzylic d, 1H, Jgem ) 12.0 Hz), 5.20 (dd, 1H, J )
10.2, 10.2 Hz), 7.17-7.39 (m, 20H, Ar-H); EI-HRMS calcd for
C46H51NO13 [M + Na]+ 848.3253, found 848.3216.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
ꢀ-D-glycopyranosyl-(1f6)-2,3,4-tri-O-benzyl-ꢀ-D-mannopyrano-
side (17). Yield 58% (Method A) and 94% (Method C); Rf 0.76
(toluene/EtOAc 1:1); [R]D +1 (c 1.0, CHCl3); 13C NMR (124.6
MHz, 30 °C, CDCl3) δ 20.7, 20.8, 24.5, 54.8, 60.5, 63.9, 68.2,
70.0, 71.4, 72.0, 72.5, 74.5, 74.7, 74.8, 75.3, 77.2, 80.2, 98.9, 100.5,
127.5, 127.5, 127.6 (3C), 127.8 (2C), 127.9 (2C), 128.3 (2C), 128.3
1
(2C), 128.3, 138.4, 138.5, 138.9, 153.2, 169.4, 169.9, 170.5; H
NMR (500 MHz, 30 °C, CDCl3) δ 2.00 (s, 3H), 2.11 (s, 3H), 2.46
(s, 3H), 3.30 (s, 3H), 3.72-3.77 (m, 2H), 3.87-3.99 (m, 4H), 4.04
(dd, 1H, J ) 1.5, 11.0 Hz), 4.22 (dd, 1H, J ) 10.0, 12.5 Hz), 4.33
(dd, 1H, J ) 6.0, 12.0 Hz), 4.41 (dd, 1H, J ) 6.0, 12.0 Hz), 4.61
(s, 2H), 4.70-4.73 (m, 4H), 4.93 (benzylic d, 1H, Jgem ) 10.5 Hz),
5.10 (d, 1H, J ) 6.5 Hz), 5.14 (dd, 1H, J ) 4.5, 10.0 Hz),
7.27-7.37 (m, 15H, Ar-H); EI-HRMS calcd for C41H47NO14 [M
+ Na]+ 800.2894, found 800.2921.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
r-D-glycopyranosyl-(1f6)-2,3,4-tri-O-benzyl-r-D-mannopyrano-
side (18). Yield 66%; Rf 0.66 (toluene/EtOAc 2:1); [R]D +60 (c
1.0, CHCl3); 13C NMR (75 MHz, CDCl3) δ 20.9, 20.9, 24.6, 54.9,
60.6, 64.0, 68.3, 70.1, 71.5, 72.1, 72.6, 74.5, 74.8, 74.9, 75.4, 77.3,
80.3, 99.0, 100.6, 127.6-128.5 (Ar-C), 138.6, 138.7, 139.0, 153.4,
1
169.6, 170.1, 170.7; H NMR (300 MHz, CDCl3) δ 2.01 (s, 3H),
2.12 (s, 3H), 2.47 (s, 3H), 3.31 (s, 3H), 3.71-3.78 (m, 2H),
3.86-4.01 (m, 5H), 4.04 (dd, 1H, J ) 1.5, 10.5 Hz), 4.22 (dd, 1H,
J ) 9.6, 12.6 Hz), 4.33 (dd, 1H, J ) 6.0, 12.0 Hz), 4.41 (dd, 1H,
J ) 6.0, 12.0 Hz), 4.61 (s, 2H), 4.67-4.74 (m, 4H), 4.93 (benzylic
d, 1H, Jgem ) 11.1 Hz), 5.10 (d, 1H, J ) 6.9 Hz), 5.14 (dd, 1H, J
) 4.2, 9.6 Hz), 7.27-7.39 (m, 15H, Ar-H); EI-HRMS calcd for
C41H47NO14 [M + Na]+ 800.2894, found 800.2906.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
r-D-glycopyranosyl-(1f2)-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-
r-D-mannopyranoside (24). Thiourea (0.043 g, 0.572 mmol) was
added to a stirred solution of 23 (0.057 g, 0.082 mmol) and 2,6-
lutidine (0.038 mL, 0.328 mmol) in CH2Cl2/MeOH (1:1, 4 mL),
and the resulting solution was heated to 35 °C. After stirring for
40 h, the mixture was diluted with CH2Cl2 (8 mL), washed
consecutively with 1 M HCl (25 mL) and H2O (25 mL), and
subjected to normal workup. FC (toluene/EtOAc 3:1 f 1:1) gave
22 (0.043 g, 0.069 mmol, 84%): Rf 0.40 (toluene/EtOAc 1:3); [R]D
+123 (c 1.0, CHCl3); 13C NMR (125.6 MHz, 30 °C, CDCl3) δ
17.7, 17.8, 20.7, 20.9, 23.5, 47.9, 48.0, 55.0, 60.0, 61.3, 62.4, 63.1,
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
ꢀ-D-glycopyranosyl-(1f4)-2,3-O-isopropylidene-r-L-rhamnopyra-
noside (19). Yield 82% (Method A) and 91% (Method C); Rf 0.64
(toluene/EtOAc 1:1); [R]D -48 (c 1.0, CHCl3); 13C NMR (124.6
MHz, 30 °C, CDCl3) δ 17.6, 20.6, 20.7, 24.7, 26.4, 28.0, 54.8,
60.8, 63.5, 63.8, 69.1, 76.0, 76.1 (2C), 77.3, 78.7, 97.9, 98.9, 109.2,
1
153.3, 169.3, 170.5, 170.6; H NMR (500 MHz, 30 °C, CDCl3) δ
1.27 (d, 3H, J ) 6.0 Hz), 1.33 (s, 3H), 1.52 (s, 3H), 2.08 (s, 3H),
2.12 (s, 3H), 2.51 (s,3H), 3.36 (s, 3H), 3.65 (dd, 1H, J ) 7.5, 9.5
Hz), 3.70 (dd, 1H, J ) 6.0, 10.0 Hz), 3.90-3.95 (m, 2H), 4.09 (d,
1H, J ) 6.0 Hz), 4.19 (dd, 1H, J ) 6.0, 12.0 Hz), 4.24 (dd, 1H, J
J. Org. Chem. Vol. 73, No. 18, 2008 7187

Olsson et al.
66.8, 68.6, 70.5, 70.9, 73.9, 77.1, 96.6, 99.8, 100.0, 100.2, 152.9,
169.4, 170.7, 171.0; 1H NMR (500 MHz, 30 °C, CDCl3) δ 1.24 (s,
3H), 1.25 (s, 3H), 2.10 (s, 3H), 2.14 (s, 3H), 2.49 (s, 3H), 3.22 (s,
3H), 3.23 (s, 3H), 3.36 (s, 3H), 3.69 (m, 1H), 3.75-3.87 (m, 4H),
3.95-4.05 (m, 3H), 4.12 (dd, 1H, J ) 6.0, 12.0 Hz), 4.25 (d, 1H,
J ) 12.0 Hz), 4.68 (dd, 1H, J ) 11.5, 11.5 Hz), 4.75 (s, 1H), 5.23
(dd, 1H, J ) 10.0, 10.0 Hz), 5.82 (d, 1H, J ) 2.0 Hz); EI-HRMS
calcd for C26H39NO16 [M + Na]+ 644.2167, found 644.2187.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-
r-D-glycopyranosyl-(1f2)-[2-acetamido-4,6-di-O-acetyl-2,3-N,O-
carbonyl-2-deoxy-ꢀ-D-glycopyranosyl-(1f6)]-3,4-O-(2,3-dimethoxy-
butane-2,3-diyl)-r-D-mannopyranoside (25). DTBMP (0.022 g,
0.107 mmol), 4 (0.022 g, 0.059 mmol), and 24 (0.022 g, 0.035
mmol) were dissolved in dry CH2Cl2 (3 mL). After stirring for 20
min in the presence of 4 Å molecular sieves under an Ar
atmosphere, the mixture was cooled to 0 °C and DMTST (0.022 g,
0.085 mmol) was added. The reaction was brought to 20 °C over
20 min and was then quenched with Et3N (0.150 mL). The mixture
was filtered through Celite and subjected to normal workup. FC
(toluene/EtOAc 3:1 f 2:1) yielded 23 (0.026 g, 0.028 mmol, 77%):
Rf 0.45 (toluene/EtOAc 1:1); [R]D +73 (c 1.0, CHCl3); 13C NMR
(125.6 MHz, 30 °C, CDCl3) δ 17.6, 17.8, 20.6 (3C), 20.7, 23.4,
24.5, 47.8, 47.9, 54.9, 59.9, 60.6, 61.9, 63.6 (2C), 67.0, 67.6, 68.5,
69.7, 70.1, 70.6, 73.4, 75.2, 76.7, 76.9, 96.8, 99.8, 99.9, 100.1,
(dd, 1H, J ) 2.0, 5.5 Hz), 3.51 (dd, 1H, J ) 8.0, 10.0 Hz),
3.79-3.83 (m, 3H), 3.90 (dd, 1H, J ) 10.0, 10.0 Hz), 3.94-3.97
(m, 2H), 4.06- 4.33 (m, 16H), 4.54 (dd, 1H, J ) 4.5, 12.5 Hz),
4.67-4.71 (m, 2H), 5.11 (d, 1H, J ) 7.5 Hz), 5.23 (benzylic d,
2H, Jgem ) 12.0 Hz), 5.29-5.33 (m, 2H), 5.55 (dd, 1H, J ) 8.0,
9.5 Hz), 5.76 (dd, 1H, J ) 9.5, 9.5 Hz), 5.81 (d, 1H, J ) 2.5 Hz),
5.94 (dd, 1H, J ) 9.5, 9.5 Hz), 7.17-7.53 (m, 22H, Ar-H), 7.83
(d, 2H, J ) 7.0 Hz), 7.88 (d, 2H, J ) 7.5 Hz), 7.94 (d, 2H, J ) 7.0
Hz), 7.98 (d, 2H, J ) 7.5 Hz).
NMR Experiments. Experiment 1: Glycosylation. Solutions
of 4 (6.0 mg, 16.0 µmol, in 0.4 mL of CH2Cl2) and 7 (5.5 mg,
11.8 µmol, in 0.4 mL of CH2Cl2) were added to a NMR tube; the
solvent was evaporated, and the NMR tube was dried under vacuum
overnight. CD2Cl2 (0.4 mL) was added, and a reference spectrum
was recorded. NIS (4.8 mg, 21.2 µmol) and AgOTf (∼0.3 mg, 1.2
µmol) were added, and the NMR tube was sealed under an argon
atmosphere. The reaction was followed by integration of signals
1
corresponding to the acetyl singlets, and H NMR spectra were
recorded during 360 min. Selected peaks: 9 (ꢀ-1f3-linkage, 300
MHz, CD2Cl2): δ 1.97, 2.11, 2.26; 10 (R-1f3-linkage, 300 MHz,
CD2Cl2): δ 2.00, 2.04, 2.06.
Experiment 2: Anomerization. Compound 9 (5.0 mg, 6.4 µmol)
was dissolved in CD2Cl2 (0.4 mL), and a reference spectrum was
recorded. A catalytic amount of AgOTf was added, and the NMR
tube was sealed under an argon atmosphere. The reaction was
followed by integration of signals corresponding to the acetyl
singlets, and 1H NMR spectra were recorded during 240 min.
Selected peaks: 9 (ꢀ-1f3-linkage, 300 MHz, CD2Cl2): δ 1.97, 2.11,
2.26; 10 (R-1f3-linkage, 300 MHz, CD2Cl2): δ 2.00, 2.04, 2.06.
Experiment 3: Anomerization in the Presence of CH3OH.
Compound 9 (5.0 mg, 6.4 µmol) was dissolved in CD2Cl2 (0.4 mL),
and a reference spectrum was recorded. CH3OH (2.0 µL, 51.0 µmol,
8.0 equiv) and an excess of AgOTf were added, and the NMR tube
was sealed under an argon atmosphere. The reaction was followed
by integration of signals corresponding to the acetyl singlets, and
1H NMR spectra were recorded under 60 min, whereafter the
solution was evaporated and FC (toluene/EtOAc 19:1f 9:1 f 6:1)
gave 7 (4.0 mg, 5.1 µmol, 80%). Selected peaks: 9 (ꢀ-1f3-linkage,
300 MHz, CD2Cl2): δ 1.97, 2.11, 2.26; 10 (R-1f3-linkage, 300
MHz, CD2Cl2): δ 2.00, 2.04, 2.06.
1
101.0, 153.1, 153.1, 169.2, 169.4, 170.1, 170.5, 170.5, 170.7; H
NMR (500 MHz, 30 °C, CDCl3) δ 1.23 (s, 3H), 1.25 (s, 3H), 2.09
(s, 3H), 2.10 (s, 3H), 2.13 (s, 3H), 2.13 (s,3H), 2.49 (s, 3H), 2.51
(s, 3H), 3.12 (s, 3H), 3.22 (s, 3H), 3.37 (s, 3H), 3.74 (dd, 1H, J )
6.5, 10.5 Hz), 3.78-3.88 (m, 4H), 3.96-4.06 (m, 4H), 4.09 (dd,
1H, J ) 2.0, 10.5 Hz), 4.19-4.20 (m, 2H), 4.24-4.30 (m, 2H),
4.45 (dd, 1H, J ) 5.5, 12.5 Hz), 4.71 (s, 1H), 4.81 (dd, 1H, J )
10.0, 12.0 Hz), 5.09 (d, 1H, J ) 7.0 Hz), 5.15 (dd, 1H, J ) 5.0,
10.0 Hz), 5.28 (dd, 1H, J ) 10.0, 10.0 Hz), 5.81 (d, J ) 3.0 Hz);
EI-HRMS calcd for C39H54N2O24 [M + Na]+ 957.2964, found
957.2974.
2-Acetamido-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-r-D-glu-
copyranosyl-(1f2)-7-O-benzyl-6-O-chloroacetyl-3,4-O-(2′,3′-
dimethoxybutane-2′,3′-diyl)-L-glycero-r-D-mannoheptapyranosyl-
(1f3)-[2,3,4,6-tetra-O-benzoyl-ꢀ-D-glucopyranosyl-(1f4)]-7-O-
acetyl-1,6-anhydro-2-O-benzyl-L-glycero-r-D-mannoheptapyranose
(27). Acceptor 2620 (0.016 g, 0.012 mmol) and donor 4 (0.018 g,
0.048 mmol) were dissolved in dry CH2Cl2 (1.5 mL). After stirring
for 30 min in presence of 4 Å molecular sieves under argon, the
mixture was cooled to 0 °C. NIS (0.011 g, 0.050 mmol) and AgOTf
(0.002 g, 0.008 mmol) were added, and the mixture was stirred for
additional 30 min. Et3N (0.10 mL) was added, and the mixture
was then filtered through Celite, washed with Na2S2O3 (10% aq, 8
mL), and subjected to normal workup. FC (toluene/EtOAc 6:1 f
3:1 f 1:1) gave 27 (0.018 g, 0.011 mmol, 92%): Rf 0.63 (toluene/
Acknowledgment. We thank the Swedish Research Council
and Science Foundation Ireland for financial support.
Supporting Information Available: General experimental
procedures, copies of spectra of compounds 2-6, 9-14, 17-25,
and 27, and X-ray crystallographic data (CIF file) for compound
4. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
EtOAc 1:1); H NMR (500 MHz, 30 °C, CDCl3) δ 1.20 (s, 3H),
1.25 (s, 3H), 2.05 (s, 3H), 2.06 (s, 3H), 2.07 (s, 3H), 2.47 (s,3H),
3.09 (s, 3H), 3.15 (s, 3H), 3.31 (dd, 1H, J ) 5.5, 10.5 Hz), 3.38
JO800971S
7188 J. Org. Chem. Vol. 73, No. 18, 2008