Halide-mediated regioselective 6-O-glycosylation of unprotected hexopyranosides with perbenzylated glycosyl bromide donors

Article abstract of DOI:10.1016/j.tet.2015.11.059

The regio- and stereoselective glycosylation at the 6-position in 2,3,4,6-unprotected hexopyranosides has been investigated with dibutyltin oxide as the directing agent. Perbenzylated hexopyranosyl bromides were employed as the donors and the glycosylations were promoted by tetrabutylammonium bromide. The couplings were completely selective for both glucose and galactose donors and acceptors as long as the stannylene acetal of the acceptor was soluble in dichloromethane. This gave rise to a number of 1,2-cis-linked disaccharides in reasonable yields. Mannose donors and acceptors, on the other hand, did not react in the glycosylation under these conditions.

Full text of DOI:10.1016/j.tet.2015.11.059

Tetrahedron 72 (2016) 415e419
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Halide-mediated regioselective 6-O-glycosylation of unprotected
hexopyranosides with perbenzylated glycosyl bromide donors
*
Dominika Alina Niedbal, Robert Madsen
Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
The regio- and stereoselective glycosylation at the 6-position in 2,3,4,6-unprotected hexopyranosides has
been investigated with dibutyltin oxide as the directing agent. Perbenzylated hexopyranosyl bromides
were employed as the donors and the glycosylations were promoted by tetrabutylammonium bromide.
The couplings were completely selective for both glucose and galactose donors and acceptors as long as
the stannylene acetal of the acceptor was soluble in dichloromethane. This gave rise to a number of 1,2-
cis-linked disaccharides in reasonable yields. Mannose donors and acceptors, on the other hand, did not
react in the glycosylation under these conditions.
Received 22 September 2015
Received in revised form 10 November 2015
Accepted 24 November 2015
Available online 27 November 2015
Keywords:
Glycosylation
Glycosyl bromide
Regioselectivity
Stannane
Ó 2015 Elsevier Ltd. All rights reserved.
Stereoselectivity
1. Introduction
been developed in order to steer the donor to only one hydroxy
group. These reagents can mediate very regioselective glycosyla-
The chemical synthesis of oligosaccharides lies at the corner-
stone of carbohydrate chemistry due to the immense biological
importance of glycans. The area has experienced significant prog-
ress over the past three decades with the development of new ef-
fective glycosyl donors, promoters and coupling strategies.1 This
has made it possible to synthesize rather large oligosaccharides
with more than 20 monosaccharides where each glycosidic linkage
is formed with excellent stereocontrol and in good yield.2 However,
the regioselectivity is still controlled by the use of partially pro-
tected glycosyl acceptors containing one free hydroxy group. These
acceptors are prepared through several protecting group manipu-
lations which add a considerable number of steps to the synthesis
of a target molecule. Accordingly, the chemical synthesis of oligo-
saccharides from monosaccharides is still quite a time-consuming
event due to the preparation of building blocks and the trans-
formation of protecting groups.
tions to either the primary hydroxy group or to the most reactive
secondary alcohol.
Bu2SnO has been employed in the glycosylation of a number of
unprotected
b-galacto- and b-glucopyranosides to afford the
(1 / 6)-linked disaccharides in good yield.5 These reactions are
believed to proceed through the 4,6-stannylene acetal of the ac-
ceptor which enhances the reactivity of the 6-position. On the
contrary, Ph2SnCl2 mediates the selective glycosylation of the 3-
position in 2,3,4,6-unprotected mannosides, glucosides and galac-
tosides.6 The same selectivity is achieved by transient masking of
the 4- and the 6-position with boronic acids in glucosides and ga-
lactosides7 while fully unprotected glucose under these conditions
gives glycosylation at position 6 due to temporary blocking of po-
sition 1, 2, 3 and 5.8 Regioselective glycosylation at position 3 in
mannosides and galactosides can also be achieved in a borinic acid-
catalyzed protocol although protection of position 6 is necessary in
this case.9,10
As a result, there is an increasing interest in the development of
regioselective glycosylations with 2,3,4,6-unprotected glycosyl ac-
ceptors.3 Although these acceptors contain both a primary and
several secondary hydroxy groups, the direct glycosylation of the
primary hydroxy group generally gives poor regioselectivity.4
Therefore, several directing agents based on tin and boron have
However, most of these procedures employ the KoenigseKnorr
glycosylation with peracylated glycosyl bromides and various silver
salts as promoters giving rise to the 1,2-trans coupling products. In
a few cases peracylated thioglycosides have been used as donors
with DMTST5c and NIS/Lewis acid7a,8 as promoters. In addition, the
halide ion-catalyzed glycosylation11 has been utilized with tin re-
agents for glycosylating methyl
(with perbenzylated glucosyl bromide)5c and methyl
position 60 (with perbenzylated galactosyl bromide).5d The latter
b
-
D
-galactopyranoside at position 6
b
-lactoside at
* Corresponding author. Tel.: þ45 4525 2151; fax: þ45 4588 3136; e-mail address:
rm@kemi.dtu.dk (R. Madsen).
http://dx.doi.org/10.1016/j.tet.2015.11.059
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

416
D.A. Niedbal, R. Madsen / Tetrahedron 72 (2016) 415e419
Table 1
two examples are interesting since a cheap glycosylation method is
employed and the product is obtained with a 1,2-cis relationship.
However, the scope and limitations of this approach have not been
thoroughly explored and we therefore decided to investigate the
halide ion-catalyzed glycosylation with a range of donors and ac-
ceptors under different conditions. Herein, we report full details of
the bromide-mediated glycosylation of the 6-position in 2,3,4,6-
unprotected hexopyranosides in the presence of Bu2SnO.
Optimization of the regioselective glycosylation
2. Results and discussion
Entry
Solvent
Temp (ꢁC)
Time (h)
Yield (%)a
1
2
3
4
5
6
CH2Cl2
THF
CH3CN
CH3CCl3
THF
20
20
20
20
40
40
40
20
20
40
0
20
20
20
20
20
20
20
20
18
18
18
18
18
18
18
18
18
8
18
18
18
18
24
72
24
72
72
40
35
30
25
45b
30b
18
46
17
10
8
35
30
48b
50
56
40
46
45
Unprotected phenyl 1-thioglycopyranosides were selected as
acceptors for these studies in line with our earlier work5a,7a since
the regioselective glycosylation would then provide a straightfor-
ward route to a number of thioglycoside building blocks that are
useful glycosyl donors. For optimizing the reaction conditions both
a glucose donor and a glucose acceptor was employed. Tetra-O-
CH3CN
CH3CCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7
8c
9c,d
10c
11c
12c,e
13e
14c,f
15c
16c
17c,e
18c,e
19c,g
benzyl-a-D-glucopyranosyl bromide (1) was prepared from the
corresponding lactol with oxalyl bromide in dichloromethane.12
Although, bromide 1 in some references has been described as
highly unstable, the compound can be purified by silica gel flash
chromatography with ethyl acetate/heptane and stored at ꢀ15 ꢁC
for months.
The regioselective coupling of 1 to phenyl 1-thio-b-D-glucopyr-
anoside (2) was performed by treating the latter with 1 equiv of
Bu2SnO in methanol followed by removal of the solvent and drying
under high vacuum. The resulting stannylene acceptor complex
was then dissolved in dichloromethane with 1.8 equiv of donor 1
and 1.8 equiv of tetra-n-butylammonium bromide. After stirring
overnight at room temperature the (1 / 6)-linked disaccharide 3
a
Isolated yield.
Product obtained as an
4 A molecular sieves were also added in the glycosylation.
Reaction performed in the absence of Bu2SnO.
With 10% of Bu2SnO.
b
c
d
e
f
a
/b
mixture.
ꢀ
was isolated in 40% yield as the pure
a anomer with unreacted
Bu4NBr was replaced with I2/DDQ.
With 2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl chloride instead of 1.
donor and acceptor as the only remaining compounds in the mix-
ture (Table 1, entry 1). This indicates that the desired reaction is
very stereo- and regioselective under these conditions. However, it
is also a rather slow transformation and the coupling was therefore
subjected to a further optimization.
The reaction in THF, acetonitrile and trichloroethane produced
slightly lower yields than in dichloromethane (entries 2e4). In-
creasing the reaction temperature gave better conversion in THF
while no improvements were observed in acetonitrile and tri-
chloroethane (entries 5e7). However, in THF and acetonitrile the
g
collidine or lutidine. Replacing the promoter with the stronger
activator I2/DDQ14 gave essentially the same yield as with Bu4NBr,
but now as a 2:3 a/b mixture (entry 14).
In all these experiments with Bu2SnO the remaining material in
the mixture was unreacted donor and acceptor. Therefore, it was
decided to extend the reaction time which produced 3 in 50% yield
after 24 h and 56% after 72 h (entries 15 and 16). Both yields were
lowered by 10% when only a catalytic amount of Bu2SnO was
employed (entries 17 and 18). Replacing bromide 1 with the cor-
responding glycosyl chloride also gave a lower yield of 3 due to
a slower conversion (entry 19).
The optimized conditions were then applied for coupling be-
tween 1 and galactose acceptor 4 which produced disaccharide 5 in
52% yield after 24 h and 58% after 72 h (Table 2, entries 1 and 2).
Again, a decrease of about 10% was observed when the glycosyla-
tion was performed with only a catalytic amount of Bu2SnO (entries
3 and 4). Galactose donor 6 was also prepared and coupled to ac-
ceptors 2 and 4 to afford disaccharides 7 and 8, respectively. The
reactions were performed with both stoichiometric and catalytic
amounts of Bu2SnO and the yields were essentially the same as
obtained with glucose donor 1 (entries 5e12). All the glycosylations
product 3 was obtained as an a/b mixture with a ratio of about 10:1,
which renders these conditions unattractive. No conversion oc-
curred in DMF while the stannylene acetal complex was not
fully soluble in diethyl ether, dioxane and toluene and therefore
only produced a 10e15% yield of 3 in these solvents (results not
shown).
Consequently, attention shifted back to dichloromethane where
ꢀ
the reaction was repeated in the presence of 4 A molecular sieves
(MS)13 which increased the yield to 46% (entry 8). When this cou-
pling was performed in the absence of Bu2SnO the yield dropped to
17% and several byproducts were now clearly visible by TLC (entry
9). This experiment shows that the stannylene acetal is essential to
form exclusively the (1 / 6)-linked glycosylation product. Higher
or lower temperature gave lower yield in the presence of Bu2SnO
(entries 10 and 11) and room temperature was therefore selected
for general use. Interestingly, the amount of Bu2SnO could be
lowered to 10% and the disaccharide 3 was still obtained in
a modest yield (entries 12 and 13). The acceptor 2 was not fully
soluble in dichloromethane upon pretreatment with only a cata-
lytic amount of Bu2SnO. This may account for the slightly lower
yield under these conditions which is about 15% higher than in the
absence of Bu2SnO (entries 9, 12 and 13). Attempts to replace
Bu2SnO with 10% of Bu2SnCl2, Ph2SnCl2 or Me2SnCl2 gave less than
25% yield of 3 (results not shown). Decomposition of the donor
occurred when molecular sieves were replaced with a base such as
under the optimized conditions gave exclusively the a-linked di-
saccharides and none of the b-isomers were detected. The regio-
selectivity was confirmed by HMBC correlations between H-10 and
C-6 in the products.
It was attempted to perform the same couplings with mannose
acceptors 9 and 10 (Fig. 1). However, the reactions between the
stannylene acetals of these acceptors and donors 1 and 6 only led to
decomposed donor and unreacted acceptor after 72 h. The stan-
nylene acetals of 9 and 10 were fully soluble in dichloromethane
and the lack of reactivity may therefore be due to the structure of

D.A. Niedbal, R. Madsen / Tetrahedron 72 (2016) 415e419
417
Table 2
Regioselective glycosylation with glucose and galactose donors and acceptors
dichloromethane or THF. This was not a limitation with methyl a-D-
glucopyranoside (17) which was fully dissolved after formation of
the tin complex. As a result, glycosylation with donor 6 could be
performed and disaccharide 18 was isolated in 52% yield after 72 h
(Scheme 1). A mannose donor, i.e. tetra-O-benzyl-a-D-mannopyr-
anosyl bromide, was also prepared, but no reaction occurred under
the optimized conditions with acceptors 2 and 4. This is not un-
expected since this donor is known to be less reactive than 1 and 6
in the halide-mediated glycosylation.17
Entry
Donor
Acceptor
Bu2SnO (%)
Time (h)
Product
Yield (%)a
Scheme 1. Regioselective glycosylation of 17.
1
2
3
4
5
6
7
8
1
1
1
1
6
6
6
6
6
6
6
6
4
4
4
4
2
2
2
2
4
4
4
4
100
100
10
24
72
24
72
24
72
24
72
24
72
24
72
5
5
5
5
7
7
7
7
8
8
8
8
52
58
42
50
48
57
39
44
44
52
38
47
In summary, we have investigated the Bu2SnO-directed glyco-
sylation of 2,3,4,6-unprotected hexopyranosides with perbenzy-
lated glycosyl bromide donors. Glucose and galactose acceptors can
be employed if they are soluble in dichloromethane with Bu2SnO
while no coupling occurred with mannose acceptors. The same was
observed with the donors where glucosyl and galactosyl bromides
participated in the glycosylation while no conversion took place
with the corresponding mannosyl bromide. With glucose and ga-
lactose donors and acceptors, the glycosylation occurred regiose-
10
100
100
10
10
9
100
100
10
10
11
12
10
a
Isolated yield of a(1 / 6)-linked disaccharides (none of the corresponding b-
isomers were detected).
lectively at position 6 to afford the
yields.
a-linked disaccharides in decent
3. Experimental section
3.1. General methods
Fig. 1. Unreactive mannose acceptors.
All reactions were performed under an argon atmosphere.
Molecular sieves were flame-dried before use. Dichloromethane
and tetrahydrofuran were taken from a PureSolvÔ solvent purifi-
cation system. Unprotected phenyl thioglycosides as well as benzyl
and pent-4-enyl glycosides were synthesized according to litera-
ture procedures.18 Tetrabutylammonium bromide was recrystal-
lized from ethyl acetate and stored at 60 ꢁC under high vacuum. TLC
was performed on aluminum plates coated with silica gel 60. The
plates were visualized with UV light or by dipping into a solution of
cerium (IV) sulfate (2.5 g) and ammonium molybdate (6.25 g) in
sulfuric acid (10%; 250 mL) followed by heating. Column chroma-
tography was carried out with HPLC grade solvents on silica gel 60
(230e400 mesh). IR spectra were measured on a Bruker ALPHA-P
FTIR spectrometer. NMR spectra were recorded on a Bruker As-
cend instrument with a Prodigy cryoprobe. Chemical shifts were
the complexes. We have previously observed that mannose gives
a lower yield than glucose and galactose in the regioselective
KoenigseKnorr glycosylation of the corresponding phenyl 1-
thioglycosides.5a A similar difference between the three mono-
saccharides was observed in the Bu2SnO-mediated tert-butyldi-
methylsilylation of the methyl glycosides at position 6.15 These
results may indicate that mannosides are less inclined to form
a 4,6-stannylene acetal than glucosides and galactosides, but in-
stead prefer a 2,3-acetal. Furthermore, these acetals can exist as
dimers and oligomers in solution16, which will probably render the
stannylene complexes of 9 and 10 unreactive in the halide-
mediated glycosylation.
Acceptors 11e16 were also prepared (Fig. 2), but unfortunately
the stannylene complexes of these were not soluble in
calibrated to the residual solvent signal in CDCl3
(dH¼7.26 ppm,
dC¼77.16 ppm) or to TMS. Assignment of 1H and 13C resonances
were based on COSY, HSQC, and HMBC experiments. Optical rota-
tions were measured with a PerkineElmer 341 polarimeter. High
resolution mass spectra were recorded on an Agilent 1100 LC sys-
tem which was coupled to a Mircromass LCT orthogonal time-of-
flight mass spectrometer.
3.2. Synthesis of glycosyl bromides 1 and 6
Oxalyl bromide (180
mL, 1.3 mmol) was added dropwise to
a solution of the corresponding 2,3,4,6-tetra-O-benzyl-
anose (540 mg, 1.0 mmol) in anhydrous CH2Cl2 (10 mL). The re-
action was stirred at room temperature for about 3 h until
D
-glycopyr-
Fig. 2. Insoluble acceptors.

418
D.A. Niedbal, R. Madsen / Tetrahedron 72 (2016) 415e419
disappearance of the starting material by TLC (EtOAc/heptane, 2:5).
The mixture was then diluted with CH2Cl2 and washed with water
and brine. The organic layer was dried with Na2SO4 and concen-
trated. The residue was purified by column chromatography
(EtOAc/heptane, 2:5) to afford the pure glycosyl bromides as syrups
(80% yield of 1 and 74% yield of 6). NMR data were in accordance
with literature values.12
3.6. Phenyl 2,3,4,6-tetra-O-benzyl-
a-D-galactopyranosyl-
(1 / 6)-1-thio- -glucopyranoside (7)
b-D
Colorless oil. Rf 0.56 (CH2Cl2/MeOH 9:1); [
CHCl3); nmax (film) 3372, 2880, 1454, 1345, 1217, 1113, 1090, 967,
834, 749, 692 cmꢀ1
dH (400 MHz, CDCl3) 7.47e7.11 (m, 25H, Ar),
a
]
D
þ0.6 (c 0.5,
;
4.83 (d, J¼11.4 Hz, 1H, OCH2Ph), 4.75 (d, J¼4.1 Hz, 1H, H-10), 4.74 (d,
J¼11.7 Hz, 1H, OCH2Ph), 4.71 (d, J¼11.7 Hz, 1H, OCH2Ph), 4.63 (d,
J¼11.7 Hz, 1H, OCH2Ph), 4.56 (d, J¼11.9 Hz, 1H, OCH2Ph), 4.46 (d,
J¼11.5 Hz, 1H, OCH2Ph), 4.42 (d, J¼9.7 Hz, 1H, H-1), 4.38 (d,
J¼11.8 Hz, 1H, OCH2Ph), 4.31 (d, J¼11.8 Hz, 1H, OCH2Ph), 3.95 (dd,
J¼9.4, 3.8 Hz, 1H, H-20), 3.93e3.82 (m, 3H, H-40, H-50, H-6a), 3.79
(dd, J¼9.6, 3.5 Hz, 1H, H-30), 3.51 (dd, J¼10.3, 4.7 Hz, 1H, H-6b),
3.47e3.35 (m, 5H, H-3, H-4, H-5, H-6a0, H-6b0), 3.28e3.19 (m, 1H, H-
2); dC (100 MHz, CDCl3) 138.7, 138.5, 138.1, 137.7, 132.8, 130e127
(Ar), 98.5 (C-10), 87.7 (C-1), 79.1 (C-30), 77.6 (C-3), 77.3 (C-40), 76.3
(C-20), 74.8 (2ꢂOCH2Ph), 73.7 (C-50), 73.5 (OCH2Ph), 73.1 (OCH2Ph),
72.0 (C-5), 71.7 (C-2), 69.7 (C-4), 69.1 (C-60), 68.9 (C-6); HRMS calcd
for C46H50O10S [MþNa]þ m/z 817.3022, found 817.3026.
3.3. General procedure for tin-mediated regioselective
glycosylation
A suspension of the unprotected hexopyranoside (0.5 mmol)
and Bu2SnO (0.5 mmol) in MeOH (3.0 mL) was heated to reflux until
a clear solution was obtained (3 h). The solvent was removed in
vacuo followed by drying under high vacuum for 6 h to give the
stannylene derivative as a colorless foam. The bromide donor
ꢀ
(0.9 mmol) and 4 A molecular sieves (300 mg) were then added to
a solution of the stannylene derivative in CH2Cl2 (2 mL). The sus-
pension was stirred at room temperature for 15 min. Tetrabuty-
lammonium bromide (0.9 mmol) was then added and the mixture
was stirred in the dark for the time indicated. The mixture was
diluted with CH2Cl2, filtered and concentrated. The crude product
was purified by column chromatography (toluene/acetone 3:1) or
(CH2Cl2/MeOH 95:5 / 90:10) to afford the pure disaccharide.
3.7. Phenyl 2,3,4,6-tetra-O-benzyl-
a-D-galactopyranosyl-
(1 / 6)-1-thio- -galactopyranoside (8)
b-D
Colorless oil. Rf 0.54 (CH2Cl2/MeOH 9:1); [
a
]
D
þ0.9 (c 0.5,
CHCl3); nmax (film) 3423, 1453, 1113, 1025, 868, 743, 693 cmꢀ1
;
dH
(400 MHz, CDCl3) 7.49e7.04 (m, 25H, Ar), 4.88 (d, J¼3.7 Hz, 1H, H-
10), 4.83 (d, J¼11.4 Hz, 1H, OCH2Ph), 4.74 (d, J¼11.8 Hz, 1H, OCH2Ph),
4.70 (d, J¼11.8 Hz, 1H, OCH2Ph), 4.64 (d, J¼11.7 Hz, 1H, OCH2Ph),
4.61 (d, J¼11.8 Hz, 1H, OCH2Ph), 4.46 (d, J¼11.4 Hz, 1H, OCH2Ph),
4.39 (d, J¼9.5 Hz, 1H, H-1), 4.37 (d, J¼11.6 Hz, 1H, OCH2Ph), 4.30 (d,
J¼11.7 Hz, 1H, OCH2Ph), 3.96 (dd, J¼9.4, 3.7 Hz, 1H, H-20), 3.93e3.82
(m, 4H, H-2, H-40, H-50, H-6a), 3.78 (dd, J¼9.6, 2.7 Hz, 1H, H-30), 3.68
(dd, J¼10.9, 5.3 Hz, 1H, H-6b), 3.59e3.37 (m, 5H, H-3, H-4, H-5, H-
6a0, H-6b0); dC (100 MHz, CDCl3) 138.6, 138.6, 138.1, 137.9, 132.8,
133e127 (Ar), 98.7 (C-10), 88.6 (C-1), 78.9 (C-30), 77.2 (C-20), 76.2 (C-
40), 74.8 (C-3), 74.7 (C-50), 73.8 (OCH2Ph), 73.5 (OCH2Ph), 72.9
(2ꢂOCH2Ph), 70.1 (C-5), 69.7 (C-2), 69.2 (C-4), 69.0 (C-60), 67.8 (C-
6); HRMS (ESI) calcd for C46H50O10S [MþNa]þ m/z 817.3022, found
817.3012.
3.4. Phenyl 2,3,4,6-tetra-O-benzyl-
a-D-glucopyranosyl-
(1 / 6)-1-thio- -glucopyranoside (3)
b-D
Colorless oil. Rf 0.54 (CH2Cl2/MeOH 9:1); [
a
]
þ0.8 (c 0.3,
D
CHCl3); nmax (film) 3318, 1454, 1114, 1026, 836, 530 cmꢀ1
;
dH
(400 MHz, CDCl3) 7.53e6.98 (m, 25H, Ar), 4.86 (d, J¼10.9 Hz, 1H,
OCH2Ph), 4.74 (d, J¼10.9 Hz, 1H, OCH2Ph), 4.69 (d, J¼10.9 Hz, 1H,
OCH2Ph), 4.67 (d, J¼3.3 Hz, 1H, H-10), 4.66 (d, J¼10.9 Hz, 1H,
OCH2Ph), 4.54 (d, J¼12.1 Hz, 1H, OCH2Ph), 4.51 (d, J¼12.1 Hz, 1H,
OCH2Ph), 4.43 (d, J¼9.5 Hz, 1H, H-1), 4.39 (d, J¼9.7 Hz, 1H, OCH2Ph),
4.38 (d, J¼9.7 Hz, 1H, OCH2Ph), 4.02e3.79 (m, 2H, H-30, H-6a),
3.78e3.35 (m, 9H, H-20, H-3, H-5, H-50, H-4, H-40, H-6b, H-6a0, H-
6b0), 3.24 (dd, J¼9.0, 8.1 Hz, 1H, H-2); dC (100 MHz, CDCl3) 138.7,
138.2, 137.9, 137.8, 132.9, 132e127 (Ar), 97.9 (C-10), 88.1 (C-1), 82.1
(C-30), 79.7 (C-20), 77.6 (C-40), 77.5 (C-3), 77.2 (C-50), 75.8 (OCH2Ph)
75.1 (OCH2Ph), 73.5 (2ꢂOCH2Ph), 72.1 (C-5), 71.7 (C-2), 70.5 (C-4),
69.0 (C-60), 68.5 (C-6); HRMS (ESI) calcd for C46H50O10S [MþNa]þ
m/z 817.3022, found 817.2997.
3.8. Methyl 2,3,4,6-tetra-O-benzyl-a-D-galactopyranosyl-
(1 / 6)- -glucopyranoside (18)
a-D
Colorless oil. Rf 0.51 (CH2Cl2/MeOH 9:1); [
a]
D þ5 (c 0.6, CHCl3);
dH (400 MHz,
nmax (film) 3381, 1452, 1114, 1024, 965, 546 cmꢀ1
;
3.5. Phenyl 2,3,4,6-tetra-O-benzyl-
a-D-glucopyranosyl-
CDCl3) 7.36e6.13 (m, 20H, Ar), 4.85 (d, J¼11.5 Hz, 1H, OCH2Ph), 4.77
(d, J¼12.0 Hz, 1H, OCH2Ph), 4.73 (d, J¼11.5 Hz, 1H, OCH2Ph), 4.71 (d,
J¼2.5 Hz, 1H, H-10), 4.65 (d, J¼11.6 Hz, 1H, OCH2Ph), 4.64 (d,
J¼3.5 Hz, 1H, H-1), 4.58 (d, J¼12.0 Hz, 1H, OCH2Ph), 4.48 (d,
J¼11.6 Hz, 1H, OCH2Ph), 4.40 (d, J¼11.8 Hz, 1H, OCH2Ph), 4.30 (d,
J¼11.8 Hz, 1H, OCH2Ph), 3.96 (dd, J¼9.4, 3.8 Hz, 1H, H-20), 3.90e3.80
(m, 4H, H-2, H-3, H-30, H-6a), 3.67e3.58 (m, 2H, H-4, H-40),
3.52e3.31 (m, 5H, H-5, H-50, H-6b, H-6a0, H-6b0), 3.29 (s, 3H, OCH3);
dC (100 MHz, CDCl3) 138.6, 138.5, 138.3, 137.6, 133e127 (Ar), 99.1 (C-
1), 98.8 (C-10), 79.1 (C-30), 76.2 (C-2), 74.8 (C-3), 74.7 (C-40), 74.3
(OCH2Ph), 73.8 (OCH2Ph), 73.6 (OCH2Ph), 73.1 (OCH2Ph), 72.3 (C-5),
72.0 (C-50), 70.0 (C-20), 69.4 (C-4), 69.3 (C-60), 69.2 (C-6); HRMS
(ESI) calcd for C41H48O11 [MþNa]þ m/z 739.3094, found 739.3082.
(1 / 6)-1-thio- -galactopyranoside (5)
b-D
Colorless oil. Rf 0.55 (CH2Cl2/MeOH 9:1); [
a
]
þ0.6 (c 0.4,
D
CHCl3); nmax (film) 3452, 1452, 1141, 1025, 881, 740, 694 cmꢀ1
;
dH
(400 MHz, CDCl3) 7.48e7.00 (m, 25H, Ar), 4.87 (d, J¼11.7 Hz, 1H,
OCH2Ph), 4.86 (d, J¼3.7 Hz, 1H, H-10), 4.75 (d, J¼10.7 Hz, 1H,
OCH2Ph), 4.74 (d, J¼10.7 Hz, 1H, OCH2Ph), 4.70 (d, J¼11.6 Hz, 1H,
OCH2Ph), 4.61 (d, J¼11.9 Hz, 1H, OCH2Ph), 4.52 (d, J¼12.1 Hz,
OCH2Ph), 4.42 (d, J¼9.7 Hz, 1H, H-1), 4.41 (d, J¼12.1 Hz, 1H,
OCH2Ph), 4.37 (d, J¼12.1 Hz, 1H, OCH2Ph), 4.00e3.68 (m, 5H, H-30,
H-40, H-5, H-6a, H-6b), 3.68e3.42 (m, 7H, H-2, H-20, H-3, H-4, H-50,
H-6a0, H-6b0); dC (100 MHz, CDCl3) 138.6, 138.2, 137.9, 137.8, 132.5,
132e127 (Ar), 98.0 (C-10), 88.9 (C-1), 81.9 (C-30), 79.6 (C-20), 77.6 (C-
5), 77.2 (C-40), 75.7 (OCH2Ph), 75.1 (OCH2Ph) 74.7 (C-3), 73.5
(2ꢂOCH2Ph), 70.6 (C-5), 70.2 (C-2), 69.2 (C-4), 68.4 (C-60), 67.8 (C-
6); HRMS (ESI) calcd for C46H50O10S [MþNa]þ m/z 817.3022, found
817.3004.
Acknowledgements
We thank The Novo Nordisk Foundation for financial support.

D.A. Niedbal, R. Madsen / Tetrahedron 72 (2016) 415e419
419
7. (a) Fenger, T. H.; Madsen, R. Eur. J. Org. Chem. 2013, 5923e5933; (b) Nishino, T.;
Ohya, Y.; Murai, R.; Shirahata, T.; Yamamoto, D.; Makino, K.; Kaji, E. Heterocycles
2012, 84, 1123e1140.
8. Kaji, E.; Yamamoto, D.; Shirai, Y.; Ishige, K.; Arai, Y.; Shirahata, T.; Makino, K.;
Nishino, T. Eur. J. Org. Chem. 2014, 3536e3539.
Supplementary data
Supplementary data (1H and 13C NMR spectra of all compounds)
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2015.11.059.
9. Gouliaras, C.; Lee, D.; Chan, L.; Taylor, M. S. J. Am. Chem. Soc. 2011, 133,
13926e13929.
10. Reference 9 also contains one example where methyl 3-O-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)-a-D-mannopyranoside is selectively glycosylated at
position 6 of the mannose residue in the presence of the borinic acid catalyst.
11. Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am. Chem. Soc. 1975, 97,
4056e4062.
References and notes
1. (a) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900e1934; (b) Smoot,
J. T.; Demchenko, A. V. Adv. Carbohydr. Chem. Biochem. 2009, 62, 161e250.
2. (a) Calin, O.; Eller, S.; Seeberger, P. H. Angew. Chem., Int. Ed. 2013, 52,
5862e5865; (b) Ishiwata, A.; Ito, Y. J. Am. Chem. Soc. 2011, 133, 2275e2291; (c)
Joe, M.; Bai, Y.; Nacario, R. C.; Lowary, T. L. J. Am. Chem. Soc. 2007, 129,
12. The quality of oxalyl bromide proved important for fast and clean formation of
1 and it is recommended to use a freshly distilled sample. Previous syntheses of
1 with oxalyl bromide have also included DMF in the reaction, but in our hands
the bromination worked equally well in the absence of the amide. See also: (a)
Matwiejuk, M.; Thiem, J. Eur. J. Org. Chem. 2011, 5860e5878; (b) Presser, A.;
ꢁ
9885e9901; (d) Fraser-Reid, B.; Lu, J.; Jayaprakash, K. N.; Lopez, J. C. Tetrahe-
€
Kunert, O.; Potschger, I. Monatsh. Chem. 2006, 137, 365e374; (c) Grayson, E. J.;
dron: Asymmetry 2006, 17, 2449e2463.
Ward, S. J.; Hall, A. L.; Rendle, P. M.; Gamblin, D. P.; Batsanov, A. S.; Davis, B. G. J.
Org. Chem. 2005, 70, 9740e9754; (d) Wessel, H.-P.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2251e2260.
€
3. Bottcher, S.; Thiem, J. Curr. Org. Chem. 2014, 18, 1804e1817.
ꢁ
ꢁ
4. (a) Uriel, C.; Gomez, A. M.; Lopez, J. C.; Fraser-Reid, B. Org. Biomol. Chem. 2012,
10, 8361e8370; (b) Yu, B.; Li, B.; Xing, G.; Hui, Y. J. Comb. Chem. 2011, 3,
404e406; (c) Kanie, O.; Barresi, F.; Ding, Y.; Labbe, J.; Otter, A.; Fosberg, L. S.;
Ernst, B.; Hindsgaul, O. Angew. Chem., Int. Ed. Engl. 1995, 34, 2720e2722.
5. (a) Maggi, A.; Madsen, R. Eur. J. Org. Chem. 2013, 2683e2691; (b) Kaji, E.; Harita,
N. Tetrahedron Lett. 2000, 41, 53e56; (c) Garegg, P. J.; Maloisel, J.-L.; Oscarson, S.
Synthesis 1995, 409e414; (d) Cruzado, C.; Bernabe, M.; Martin-Lomas, M. Car-
bohydr. Res. 1990, 203, 296e301; (e) Murase, T.; Kartha, K. P. R.; Kiso, M.; Ha-
segawa, A. Carbohydr. Res. 1989, 195, 134e137.
13. Lemieux, R. U.; Driguez, H. J. Am. Chem. Soc. 1975, 97, 4069e4075.
14. Kartha, K. P. R.; Aloui, M.; Field, R. A. Tetrahedron Lett. 1996, 37, 8807e8810.
15. Bredenkamp, M. W. S. Afr. J. Chem. 1995, 48, 154e156.
16. Grindley, T. B. Adv. Carbohydr. Chem. Biochem. 1998, 53, 17e142.
17. Rachaman, E. S.; Eby, R.; Schuerch, C. Carbohydr. Res. 1978, 67, 147e161.
18. (a) Schmidt, T. H.; Madsen, R. Eur. J. Org. Chem. 2007, 3935e3941; (b) Clausen,
M. H.; Jørgensen, M. R.; Thorsen, J.; Madsen, R. J. Chem. Soc., Perkin Trans. 1 2001,
ꢂ
€
543e551; (c) Pedretti, V.; Veyrieres, A.; Sinay, P. Tetrahedron 1990, 46, 77e88.
6. Muramatsu, W.; Yoshimatsu, H. Adv. Synth. Catal. 2013, 355, 2518e2524.