A general and diastereoselective synthesis of 1,2-cis-hexofuranosides from 1,2-trans-thiofuranosyl donors

Article abstract of DOI:10.1002/(SICI)1099-0690(200004)2000:8<1423::AID-EJOC1423>3.0.CO;2-9

The general formation of 1,2-trans-thioglycofuranosides derived from D- galactose, D-glucose and D-mannose was readily accomplished starting from the corresponding alkyl glycofuranosides via per-O-acetyl-hexofuranoses as key synthons. Glycosidation of ethyl or phenyl perbenzylated 1,2-trans- thiofuranosides afforded disaccharides containing a nonreducing 1,2-cis- hexofuranosyl unit, i.e. α-D-galactosyl, α-D-glucosyl or β-D-mannosyl, with interesting diastereoselectivities. Activation of the thiofuranosyl donors was performed by N-iodosuccinimide and a catalytic amount of tin(II) trifluoromethanesulfonate.

Full text of DOI:10.1002/(SICI)1099-0690(200004)2000:8<1423::AID-EJOC1423>3.0.CO;2-9

FULL PAPER
A General and Diastereoselective Synthesis of 1,2-cis-Hexofuranosides from
1,2-trans-Thiofuranosyl Donors
[a]
[a]
[a]
`
Muriel Gelin, Vincent Ferrieres, and Daniel Plusquellec*
Dedicated to Professor Dr. Pierre Sinay¨ on the occasion of his 62nd birthday
Keywords: Carbohydrates / Glycofuranosides / Thiofuranosides / Glycosylation
The general formation of 1,2-trans-thioglycofuranosides de-
ducing 1,2-cis-hexofuranosyl unit, i.e. α-
D-galactosyl, α-D-
rived from -galactose, -glucose and -mannose was read- glucosyl or β-D
D
D
D
-mannosyl, with interesting diastereoselectivi-
ily accomplished starting from the corresponding alkyl glyco- ties. Activation of the thiofuranosyl donors was performed by
furanosides via per-O-acetyl-hexofuranoses as key synthons. N-iodosuccinimide and a catalytic amount of tin(II) trifluoro-
Glycosidation of ethyl or phenyl perbenzylated 1,2-trans-
methanesulfonate.
thiofuranosides afforded disaccharides containing a nonre-
Introduction
furanosyl trichloroacetimidates[28–30] and n-pentenyl fur-
anosides[31,32] were proposed regarding their ability to yield
target saccharides. Owing to the presence of participating
protecting groups at the 2-position of the donor, 1,2-trans-
furanosides were generally obtained with complete diaster-
eoselectivity. Similar results were published by Hindsgaul et
al.[33] by cyclization of unprotected O,S-acetals[34] promoted
by mercuric salts.
The glycobiology of hexoses in their furanoid form is be-
coming a topic of increasing interest since the striking pres-
ence of -galactofuranosyl (-Galf) residues in glycoconju-
gates found in archaebacteriae,[1,2] classical prokaryotes,[3]
protozoae[4–6] or fungi[7] is now well established. These
microorganisms are able to elaborate polysaccharides con-
taining furanosides, for instance the backbone of the arabi-
nogalactan of Mycobacterium tuberculosis,[8,9] but the galac-
tofuranosyl moieties can also coexist with hexopyranosides
either as terminal nonreducing units[4,7] or as part of the
core of oligosaccharides.[4–6] In Trypanosoma cruzi glyco-
proteins,[4] the β--Galf unit is the epitope involved in re-
cognition phenomena.[4,10] Moreover, recent NMR studies
showed the presence of galactofuranosyl residues with the
opposite α-configuration, in Leishmania,[6] Penicillium[11] or
Clostridium[12] species. In contrast to the galacto-conjugates,
the nucleotide-sugar Agrocine 84,[13,14] a natural antibiotic
that controls the plant cancer crown disease,[13] is notably
characterized by a glucofuranose moiety whose anomeric
configuration has not yet been clearly determined. Since the
biosynthesis of glycoconjugates containing hexofuranosides
seems to be restricted to lower organisms, it is assumed that
compounds bearing such units could be strongly antigenic[4]
and may be useful targets for therapy in fungal and para-
sitic diseases.
As part of our program dealing with the synthesis of di-
and oligosaccharides containing 1,2-cis-hexofuranosyl en-
tities,[29] we needed a general route to stable hexofuranosyl
donors bearing nonparticipating protecting groups. How-
ever, furanosides are generally characterized by lower an-
omeric effects,[35] thus rendering preparation of α--glucofu-
rano-type derivatives more difficult than their pyranosidic
counterparts. On the other hand, access to β--mannofur-
ano-type isomers is obviously hindered by high steric ef-
fects. Nevertheless, we assumed that 1,2-trans-furanosyl
donors may lead to the corresponding 1,2-cis-furanosides
provided that the latter: (i) are formed under kinetically
controlled conditions, and (ii) do not anomerize in situ into
the thermodynamically more stable 1,2-trans-furanosides.
In this context, and owing to the versatility of thioglycos-
ides as ‘‘universal building blocks’’ and glycosyl donors,[36]
we describe herein: (i) a quite general entry into perbenzyl-
ated aryl or alkyl 1,2-trans-thiofuranosides derived from -
galactose, -glucose and -mannose, and (ii) their behavior
in glycosylation reactions for stereoselectively synthesizing
disaccharides containing an α--galacto-, α--gluco- or β-
-mannofuranoside as the nonreducing unit.
Despite significant advances in the synthesis of complex
oligosaccharides, construction of O-furanosidic linkages
from hexoses remains a challenging task. Various ap-
proaches were recently proposed as alternatives to the
Koenigs-Knorr method.[15] Thus, 1-O-acylfuranoses,[16,17] 1,2-
orthoesters,[18,19] 1,2-cyclic sulfites,[20] furanoid glycals,[21,22]
phenyl 1-seleno glycosides[23] or ethyl 1-thioglycosides,[24–27]
Results and Discussion
Preparation of Perbenzylated 1,2-trans-Thiofuranosides
[a]
´
Ecole Nationale Superieure de Chimie de Rennes,
We recently demonstrated the versatile utility of alkyl
hexofuranosides[37] as efficient starting materials for glyco-
furanosyl donors.[29] Octyl β--galactofuranoside (1), read-
CNRS ESA 6052, Laboratoire de Chimie Organique et des
Substances Naturelles,
´ ´
Avenue du General Leclerc, F-35700 Rennes, France
Eur. J. Org. Chem. 2000, 1423Ϫ1431
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0408Ϫ1423 $ 17.50ϩ.50/0
1423

`
M. Gelin, V. Ferrieres, D. Plusquellec
FULL PAPER
ily obtained in a one-step procedure from -galactose[37]
was benzylated under standard conditions and the resulting
derivative 2 submitted to mild acetolysis in order to avoid
either debenzylation or ring expansion of the five-mem-
bered ring to pyranoid compounds (Scheme 1). According
to the procedure of Ferrier,[38] the thiogalactofuranoside 4
was obtained in a disappointing 40% yield, probably be-
cause of the lability of benzyl groups in the presence of the
boron trifluoride diethyl ether complex (BF3 OEt2). More-
over, the absence of participating group at the 2-position
warranted the formation of a mixture of both anomers in
nearly equal amounts. Although each anomer was chroma-
tographically isolated, perbenzylated phenyl (4β) and ethyl
1-thiogalactofuranosides (8β), were better synthesized from
the penta-O-acetyl-galactofuranose (5)[39] as precursor. Re-
action of 5 with thiophenol or ethanethiol and BF3 OEt2 as
promoter afforded exclusively the β-thiogalactofuranosides
6β and 7β in 81% and 55% yields, respectively. Methanolysis
under Zemplen conditions followed by standard benzyl-
ation gave the required products 4β and 8β in high yields.
Scheme 2. Preparation of gluco- and mannofuranosyl donors 11β
and 14α, respectively: (i) PhSH, BF3 OEt2, CH2Cl2, 10: 70% (α/β ϭ
1:9); 13: 90% (α/β ϭ 15.7:1); (ii) a. NaOMe, MeOH; b. BnBr, NaH,
DMF, 11β: 81%; 14α: 73%
characterized by a small coupling constant between H-1
and H-2. In O-furanosides, this value is generally lower
than 1 Hz[40] but the presence of a sulfur atom at the anom-
eric position substantially increases J1,2 to almost 2 Hz. A
similar difference is also observed between O- and S-pyr-
anosides.[41] Nevertheless, as in the case of O-furanosides,[40]
compounds 4β, 8β and 11β are all levorotatory. The manno-
isomer 14α exhibits an exceptionally high value for J1,2, i.e.
7.2 Hz, but the 1,2-trans configuration was strengthened by
the positive value of optical rotation according to Hud-
son’s rules.[40]
As expected, alkyl hexofuranosides are interesting start-
ing materials for the stereospecific synthesis of novel per-
benzylated 1,2-trans-thiohexofuranosides. Moreover, while
the preparation of phenyl 1-thio-α--galactofuranoside ac-
cording to the procedure of Wolfrom et al.[42] did not suc-
ceed, or afforded the expected product in yields lower than
30%,[43] the present methodology was efficiently applied to
the synthesis of the corresponding β-anomer and was ex-
tended to other hexose derivatives and to alkyl or aryl
thiol acceptors.
Glycosylation Reactions
With the thioglycosides 4β, 8β, 11β and 14α in hand, we
then performed the glycosylation of the partially protected
monosaccharides A, B and C as representative glycosyl ac-
ceptors (Scheme 3). The behavior of perbenzylated phenyl
1-thio-β--glucofuranoside (11β) towards acceptor A in
dichloromethane was examined with a variety of promoters.
Simple electrophilic sources such as iodine and N-iodosuc-
cinimide (NIS) afforded disaccharide 15a in moderate yields
and selectivities. The reaction time significantly decreased
when activation of the thiofuranoside was achieved by NIS
and a catalytic amount of trimethylsilyl trifluoromethanes-
Scheme 1. Synthesis of galactofuranosyl donors 4 and 8 from octyl
β--galactofuranoside 1: (i) BnBr, NaH, DMF (82%); (ii) Ac2O,
H2SO4, CH2Cl2 (81%); (iii) PhSH, BF3.OEt2, CH2Cl2, 4: 40% (α/
β ϭ 1:1); 6β: 81%; (iv) see ref.[39]; (v) EtSH, BF3 OEt2, CH2Cl2
(55%); (vi) a. NaOMe, MeOH; b. BnBr, NaH, DMF, 4β: 80%; 8β:
74%
The same strategy was further spread out for the prepara- ulfonate (TMSOTf) at 0 °C but in a disappointing yield
tion of the gluco- and manno-derivatives 11β and 14α (Table 1, entry 1). Both yield and stereoselectivity were sig-
(Scheme 2). Thioglycosidation reactions of peracetylated nificantly improved in the presence of NIS and the mild
furanoses[39] 9 and 12 yielded anomeric mixtures of 10 and stannous trifluoromethanesulfonate [Sn(OTf)2], in a typical
13 (1,2-trans/1,2-cis ഠ 9–15:1). However, subsequent pro- ratio 11β/A/NIS/Sn(OTf)2 1.2:1:1.2:0.1 (entry 2), and in the
tecting group manipulation allowed simple purification by presence of molecular sieves (entry 3). These results show
column chromatography on silica gel of the desired tetra- that the efficiency and diastereocontrol of the glycosylation
O-benzylated 1,2-trans phenyl thiofuranosides 11β and 14α. reactions are highly sensitive to acidic conditions and that
1
Anomeric configurations were determined by H NMR controlling this parameter allowed the selective synthesis of
spectroscopy and corroborated by optical rotation measure- the target 1,2-cis-furanoside. From this favorable data, we
ments. Thus, β-galacto- and β-glucothiofuranosides are attempted glycosylation of the more hindered acceptors B
1424
Eur. J. Org. Chem. 2000, 1423Ϫ1431

A General and Diastereoselective Synthesis of 1,2-cis-Hexofuranosides
FULL PAPER
Table 1. Reaction conditions for the selective synthesis of disaccharides containing 1,2-cis-hexofuranosyl units
[a]
˚
Entry
Donor
ROH
Solvent
Promoter
(1.2:0.1)
4A, MS
Time
(min)
Product
Yield
(%)
α/β
1
11β
11β
11β
11β
11β
4β
A
A
A
B
C
A
A
B
C
B
C
A
A
A
A
B
C
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
NIS/TMSOTf
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/TMSOTf
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
NIS/Sn(OTf)2
–
5
15a
15a
15a
15b
15c
16a
16a
16b
16c
16b
16c
16a
16a
17a
17a
17b
17c
14
59
84
87
68
89
84
81
83
82
70
60
54
74
90
87
92
3.8:1
4.9:1
5.7:1
4.6:1
2.1:1
1:19
5.3:1
3.3:1
1.7:1
3.0:1
1.5:1
1:1
2
–
15
10
10
10
5
3
ϩ
ϩ
ϩ
–
4
5
6
7
4β
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
–
10
20
12
20
12
1260
10
10
10
12
11
8
4β
9
4β
10
11
12
13
14
15
16
17
8β
8β
4β
4β
1:4
14α
14α
14α
14α
6.7:1
1:3.3
1:2.3
1:1.9
ϩ
ϩ
ϩ
[a]
MS: molecular sieves.
The relative relationship between H-1Ј and H-2Ј is based
on the assumption of a large coupling constant between
these two nuclei (J1Ј,2Ј ϭ 4.0–4.3 Hz) and a chemical shift
for C-1Ј at δ ϭ 100.5–103.0 for the α-glucofuranosyl deriv-
atives, while smaller values of J1Ј,2Ј (Ͻ 1 Hz) and lower-field
signals (δC–1Ј ϭ 107.3–108.7) are characteristic of minor
β-products.
Similar results were also obtained when optimized condi-
tions were applied to the galactofuranosyl donors 4β and
8β. As previously observed when activation of the thiofur-
anoside was performed by NIS/TMSOTf in the absence of
molecular sieves, the β--galactofuranoside corresponding
to 16a was selectively synthesized (Table 1, entry 6).
On the other hand, activation of the furanosyl donors
under milder conditions afforded the desired disaccharides
16a–c in near 80% yields and with acceptor-dependant dia-
stereoselectivities, but still in favor of the more hindered
1,2-cis-furanosides (entries 7–11). It is also noteworthy that,
while phenyl thiopyranosides are generally less reactive than
ethyl thiopyranosides,[44] the phenyl (4β) and ethyl thiogly-
cofuranosides (8β) reacted quite similarly and gave the di-
saccharides 16b and 16c in good yields and selectivities (ent-
ries 8,10 and 9,11). Moreover, we also studied glycosidation
of donor 4β in participating solvents[45,46] with A as the
model acceptor. As expected, marked effects on the α/β ra-
tio were observed since the disaccharide 16a was obtained
Scheme 3. Stereoselective synthesis of 1,2-cis-glycofuranosides at
0 °C; for reagents and conditions, see Table 1
and C. Although steric effects lowered the α/β ratio, the without any selectivity in diethyl ether (entry 12) while 16aβ
disaccharides 15b and 15c were obtained within only a few was predominant in the anomeric mixture when the reac-
minutes at 0 °C in good yields and interesting diastereose- tion was performed in acetonitrile (entry 13). The data
lectivities towards the α-anomers (entries 4 and 5).
shows that optimized yields and α-stereocontrol still re-
The compounds 15a–c were purified by flash-chromato- quired nonparticipating solvents, e.g. dichloromethane. Fi-
graphy and 15bα was isolated as a pure anomer. The latter nally, the relative stereocontrol assignment of the galactofu-
was then easily characterized on the grounds of signals ranosides was made by 1H and 13C NMR spectroscopy
1
identified by COSY and heteronuclear H-13C 2D experi- (Table 2, Table 3 and Table 4) starting from disaccharides
ments (Table 2, Table 3 and Table 4). This analysis was the 16cα and 16cβ, which were separated by column chromato-
starting point to unequivocally assign signals for other di- graphy. The former is characterized by a large H-1Ј–H-2Ј
saccharides 15a,c.
coupling constant (J1Ј,2Ј ϭ 4.5 Hz) and by a chemical shift
Eur. J. Org. Chem. 2000, 1423Ϫ1431
1425

`
M. Gelin, V. Ferrieres, D. Plusquellec
FULL PAPER
1
Table 2. H NMR spectroscopic data (δ, ppm; nd: not determined) for disaccharides 15–17
Product
δ (ppm)
H-1Ј
H-1
H-2
H-3
H-4
H-5
H-6a
H-6b
H-2Ј
H-3Ј
H-4Ј
H-5Ј
H-6Јa
H-6Јb
15aα[a]
15aβ[a]
4.91
4.90
4.83
4.86
5.46
5.47
5.13
5.01
3.93
3.92
3.81
3.77
3.52
3.50
5.03
5.03
3.97
4.01–
4.09
3.98
4.07–
4.09
3.81
4.27
4.01–
4.09
4.24
4.07–
4.09
4.08
4.33
4.35
3.92
4.01–
4.09
4.01
4.10
3.83
3.88
3.68
3.65
15bα[b]
15bβ[b]
5.52
5.54
4.30
4.29
4.53
4.51
4.27
4.15
4.06
3.96
3.86
3.90
3.70
3.56
5.12
5.11
4.35
4.35
3.83
3.88
3.67
3.70
15cα[c]
15cβ[c]
4.62
4.57
3.55
3.98
3.73–
3.76
3.75–
3.82
5.03
5.05
4.29–
4.33
4.18
3.79–
3.82
3.83
3.84–
3.90
3.63–
3.67
3.92
3.92
4.03
3.76
3.63
5.57
5.34
4.19
3.98
3.84–
3.90
3.91–
4.00
3.68
3.76
3.71
3.73–
3.76
3.67
3.57
3.52
3.44–
3.49
4.77
4.89
4.30
3.91–
4.00
5.44
5.48
4.55–
4.58
nd
3.75–
3.82
3.73
3.76
3.86
3.63–
3.67
3.48
3.47
3.63
3.91–
4.00
4.04
4.04
4.06
4.21–
4.25
4.24
4.01
4.29–
4.33
nd
16aα[a]
16aβ[a]
16bα[b]
4.87
4.96
5.52
4.95
5.06
5.05
3.97
4.15
3.96
3.62
3.71
3.64
3.56
3.66
3.58
16bβ[b]
16cα[c]
5.54
4.61
nd
3.56
nd
nd
nd
5.20
5.51
nd
3.84
4.13
3.79–
3.82
4.25
3.78
3.71
nd
3.62
nd
3.58
4.01
3.79–
3.82
3.74
3.79–
3.82
3.61–
3.63
3.77
3.79
3.78
3.79–
3.82
3.61–
3.63
3.51
3.54
3.74
4.14
16cβ[c]
4.58
3.54
3.89
5.29
3.95
3.99
3.67
3.56
3.44
17aα[a]
17aβ[a]
17bα[b]
4.93
4.85
5.53
4.87
4.84
4.31
5.45
5.47
4.58
5.10
4.95
4.27
3.91
3.99
4.03–
4.08
4.03–
4.12
3.75–
3.79
3.86
5.15
5.08
5.22
4.02
3.92
4.03–
4.08
3.88
4.25
4.21
4.22
4.16
4.10
4.23
4.07
4.04
4.03–
4.08
4.03–
4.12
4.00
3.87
3.86
3.86
3.65
3.67
3.64
17bβ[b]
17cα[c]
17cβ[c]
5.52
4.60
4.59
4.27
3.51
3.52
4.44
3.94
3.98
4.23
3.62
3.75
3.93
3.74
3.56
5.11
5.66
5.21
4.20
4.17
4.11
4.15
4.07
3.98
3.86
3.77
3.80
3.73
3.49–
3.54
3.46–
3.48
3.91
3.68
3.49–
3.54
3.70
3.46–
3.48
3.77
[a]
δ ϭ 7.19–7.38 (C6H5), δ ϭ 4.27–5.00 (CH2Ph), δ ϭ 3.17–3.37 (OCH3), δ ϭ 1.94–2.08 (CH3CO). – [b] δ ϭ 7.18–7.39 (C6H5), δ ϭ 4.39–
[c]
4.92(CH2Ph), δ ϭ 1.16–1.52 [C(CH3)2]. – δ ϭ 7.13–7.36 (C6H5), δ ϭ 4.23–5.08 (CH2Ph), δ ϭ 3.35–3.41 (OCH3).
1
Table 3. H NMR spectroscopic data (J, Hz, nd: not determined) for disaccharides 15–17
Product
J (Hz)
1,2
2,3
3,4
4,5
5,6a
5,6b
6a,6b
1Ј,2Ј
2Ј,3Ј
3Ј,4Ј
4Ј,5Ј
5Ј,6Јa
5Ј,6Јb
6Јa,6Јb
15aα
15aβ
15bα
15bβ
15cα
15cβ
16aα
16aβ
16bα
16bβ
16cα
16cβ
17aα
17aβ
17bα
17bβ
17cα
17cβ
3.6
3.7
5.0
5.0
3.9
3.2
3.6
3.8
5.0
5.0
3.9
3.6
3.6
3.6
5.0
5.0
4.1
3.6
10.2
10.2
2.4
2.4
9.5
nd
10.2
9.5
2.4
nd
9.6
9.2
10.2
9.0
2.4
2.0
9.6
9.6
9.6
9.5
8.0
7.9
9.2
nd
9.4
9.6
nd
7.9
8.3
9.2
9.8
9.5
7.9
8.0
8.9
9.5
10.1
9.6
1.9
1.8
nd
4.4
1.9
6.0
1.9
2.0
nd
5.4
2.3
6.2
nd
nd
nd
2.4
6.3
1.8
6.7
6.4
nd
2.8
5.8
2.1
nd
nd
nd
2.0
7.2
7.7
6.2
6.3
4.8
11.3
11.3
9.8
10.0
10.7
nd
11.4
11.4
10.0
nd
nd
nd
11.3
11.3
10.6
9.7
10.8
nd
4.1
4.1
nd
6.0
4.4
5.9
4.8
5.0
5.4
7.3
7.0
7.1
6.5
6.8
5.6
3.8
4.2
2.8
4.6
3.9
3.8
6.4
8.8
7.5
9.2
7.7
9.4
6.7
3.2
6.1
3.3
4.5
3.9
8.2
9.0
6.8
8.8
8.6
9.5
2.0
1.8
2.2
2.0
nd
1.9
4.0
6.6
4.1
nd
4.6
7.5
1.7
Ͻ 1
1.8
1.1
1.7
1.9
6.4
5.4
6.5
5.5
6.2
4.5
6.3
5.4
6.3
nd
6.5
3.1
5.9
4.4
6.0
4.2
5.7
nd
10.5
10.5
10.5
10.6
10.2
10.5
10.4
10.4
10.3
nd
10.0
10.5
10.7
10.7
10.6
10.5
10.5
10.7
Ͻ 1
4.3
3.7
nd
Ͻ 1
4.0
3.5
nd
7.5
3.3
7.6
nd
6.0
2.0
3.9
4.7
4.3
4.6
4.0
4.3
nd
Ͻ 1
4.2
10.1
1.03
nd
1.9
nd
9.2
9.7
10.1
1.8
1.4
10.0
9.5
Ͻ 1
4.3
Ͻ 1
4.5
Ͻ 1
3.6
4.6
1.4
6.5
6.8
nd
4.8
4.2
4.5
4.1
2.1
5.2
for the anomeric center of the nonreducing moiety at δ ϭ furanosyl trichloroacetimidate as donor and Sn(OTf)2 as
101.9, while the corresponding NMR values for the β-an- catalyst, was specifically achieved with retention of config-
omer (J1Ј,2Ј Ͻ 1 Hz, δC-1Ј ϭ 105.9) are indicative of the trans uration on the mannosyl moiety. This data was partly cor-
relationship between H-1Ј and H-2Ј. Compounds 16a and roborated in the present study since the perbenzylated
16b were then fully analyzed by comparison with 16c.
phenyl α-thiomannofuranoside 14α reacted with acceptor
To demonstrate the scope of this methodology, we next A, with NIS/Sn(OTf)2 as promoter but in the absence of
attempted the preparation of disaccharides containing a β- molecular sieves (Table 1, entry 14), to yield selectively the
-mannofuranosyl unit which are more difficult to synthes- less hindered disaccharide 17aα. Nevertheless, all other re-
ize. Preliminary work from our laboratory[29] showed that actions carried out in the presence of an acid scavenger af-
glycosylation of A, with 2,3,5,6-tetra-O-benzyl-α--manno- forded diastereoselectively the desired 1,2-cis compounds
1426
Eur. J. Org. Chem. 2000, 1423Ϫ1431

A General and Diastereoselective Synthesis of 1,2-cis-Hexofuranosides
FULL PAPER
Table 4. 13C NMR spectroscopic data (δ, ppm) for disaccharides 15–17
Product
δ (ppm)
C-1Ј
C-1
C-2
C-3
C-4
C-5
C-6
C-2Ј
C-3Ј
C-4Ј
C-5Ј
C-6Ј
15aα
15aβ
15bα
15bβ
15cα
15cβ
16aα
16aβ
16bα
16bβ
16cα
16cβ
17aα
17aβ
17bα
17bβ
17cα
17cβ
96.5
96.4
96.3
96.3
97.6
98.1
96.3
96.5
96.3
96.3
97.5
98.1
96.7
96.2
96.4
96.3
97.8
98.0
70.9
70.9
70.6
70.6
80.1
79.6
71.0
70.8
70.7[a]
71.2[a]
80.2
79.9
70.9
71.1
70.6
70.7
79.9
79.6
70.4
70.3
70.7
70.6
81.8
80.6
70.3
70.2
70.7[a]
71.3[a]
81.6
80.1
70.4
70.3
70.6
70.4
81.7
80.6
68.9
69.1
70.7
71.0
75.8
75.7
69.4
69.1
70.6[a]
71.7
76.2
74.1
68.7
69.4
70.8
70.8
75.3
76.7
68.1
68.4
65.5
67.4
69.5
68.9
68.1
68.4
65.4
67.7
69.3
70.0
68.1
68.7
65.7
67.2
69.8[a]
70.0
65.8
66.8
66.3
66.9
69.4
69.9
65.8
65.9
65.9
66.1
69.6
68.7
65.9
67.1
67.4
65.4
69.6[a]
68.0
100.5
108.0
100.9
107.3
103.0
108.7
100.1
106.7
100.3
106.1
101.9
105.9
105.9
100.9
107.2
99.7
83.5
85.2
83.5
85.0
81.3
85.6
84.1
88.1
83.9
87.8
82.2
87.9
84.4
80.5
85.2
80.2
84.7
80.6
82.0
80.7
82.1
80.9
81.9
80.0
80.8[a]
82.8
80.8
82.8
80.0
82.8
78.2
75.8
78.3[a]
75.8
77.8
75.2
77.1
80.3
77.0
80.2
77.5
80.0
80.7[a]
81.1
80.6
80.9
79.3
82.9
78.5
78.2
78.2[a]
78.4
78.2
77.7
76.7
76.4
76.5
76.5
76.7
75.8
79.6
76.3
79.4
76.4
77.3
77.1
76.3
76.7
76.1
76.7
76.2
76.2
71.6
70.8
71.6
71.1
71.6
70.1
70.3
70.9
70.5
70.5
70.6
71.6
71.0
69.7
70.2
69.7
70.6[a]
69.0
106.4
100.9
[a]
Signals may be interchanged.
ing to ref.[37c] and compounds 5, 9 and 12 according to ref.[39] All
reactions were performed under nitrogen. – TLC analyses were car-
ried out on precoated nonactivated plates (E. Merck 60 F254) with
detection by UV absorption (254 nm), when applicable, and char-
ring with 5% H2SO4 in EtOH. – For column chromatography, E.
Merck 60H (5–40 µm) Silica Gel was used. – Optical rotations were
determined with a Perkin–Elmer 341 polarimeter at 20 °C using a
17a–17c in almost quantitative yields and with interesting β/
α ratios from 1.9:1 to 3.3:1 (entries 15–17). Molecular sieves
hence appeared to be essential for limiting in situ anomeriz-
ation of 17β to the more stable anomers 17α. These results
therefore complement those obtained through 1-O-al-
kylation of 2,3:5,6-di-O-isopropylidene--mannose.[47] The
β-configuration of the mannosyl moieties was ascertained
by NMR spectroscopy (Table 2, Table 3 and Table 4) from
compounds 17bβ and 17cβ, which were isolated by column
1
1 dm cell. – H and 13C NMR spectra were recorded on a Bruker
ARX 400 spectrometer at 400 and 100 MHz, respectively. Chemical
shifts are given in ppm (δ). CDCl3 and TMS were used as solvent
chromatography. Although the coupling constants between and internal standard, respectively. – Microanalyses were per-
formed by the Service de Microanalyses de lЈICSN (Gif sur
Yvette, France).
H-1Ј and H-2Ј did not allow us to differentiate the α- from
the β-mannofuranoside, the values observed for signals cor-
responding to the anomeric center of the nonreducing end
were representative of the postulated configuration. Indeed,
C-1Ј of the 1,2-trans isomers resonates at δ ϭ 105.9–107.2
while C-1Ј of the target 1,2-cis compounds 17aβ, 17bβ and
17cβ is shifted by approximately 5–6 ppm to higher field.
In conclusion, we have developed an efficient route to
1,2-trans-thiohexofuranosides which may be applied to the
preparation of a wide range of alkyl or aryl thiofuranosyl
donors. These latter were activated under very mild condi-
tions using NIS/Sn(OTf)2 as a new promoter of thioglycos-
ides. Glycosidation reactions of these donors interestingly
Octyl 2,3,5,6-Tetra-O-benzyl-β-D-galactofuranoside (2): To a cooled
(0 °C) solution of octyl β--galactofuranoside (1)[37] (7.34 g,
25.1 mmol) in DMF were successively added a 60% dispersion of
sodium hydride in mineral oil (4.82 g, 120.5 mmol) and, after
30 min, benzyl bromide (14.3 mL, 120.3 mmol). After stirring over-
night at room temp., the reaction was quenched by adding meth-
anol. The solvent was then removed under reduced pressure and
the resulting crude oil partitioned between ethyl acetate (150 mL)
and water (20 mL). The organic layer was washed with sat. aq.
NaCl, dried (MgSO4), concentrated and purification by flash-chro-
yielded 1,2-cis-hexofuranosides with good to high diaster- matography (light petroleum/diethyl ether, 9:1) gave 2 (13.39 g,
82%) as a colorless oil. – TLC (light petroleum/ethyl acetate, 4:1):
Rf ϭ 0.44. – [α]D ϭ –48.1 (c ϭ 1.06, CH2Cl2). – 1H NMR: δ ϭ
0.87 (br. t, J ϭ 6.9 Hz, 3 H, CH3), 1.23–1.33 (m, 10 H, CH2), 1.53–
eoselectivities, even for the synthesis of β--mannofuranos-
ides. Mechanistic studies for a better understanding of the
progress of glycosylation reactions from thiofuranosides
and the synthesis of analogues of natural glycoconjugates
are currently under investigation.
2
1.60 (m, 2 H, OCH2CH2), 3.37 (dt, J ϭ 9.7 Hz, 3J ϭ 6.7 Hz, 1 H,
OCH2CH2), 3.66 (dt, 3J ϭ 6.8 Hz, 1 H, OCH2CH2), 3.68 (dd,
J6a,6b ϭ 9.9 Hz, J6a,5 ϭ 5.0 Hz, 1 H, H-6a), 3.72 (dd, J6b,5 ϭ 6.3 Hz,
H-6b), 3.76–3.80 (m, 1 H, H-5), 3.98 (dd, J2,3 ϭ 3.4 Hz, J1,2
ϭ
1.4 Hz, 1 H, H-2), 4.01 (dd, J3,4 ϭ 7.2 Hz, 1 H, H-3), 4.12 (dd,
J4,5 ϭ 3.1 Hz, 1 H, H-4), 4.27–4.74 (m, 8 H, CH2Ph), 5.04 (br. s, 1
H, H-1), 7.28–7.40 (m, 20 H, C6H5). – 13C NMR: δ ϭ 14.1 (CH3),
22.7, 26.2, 29.3, 29.4, 29.5 (CH2), 31.8 (OCH2CH2), 67.6 (C-6),
71.0, 71.8, 72.0, 72.9, 73.3, 73.4 (OCH2CH2, CH2Ph), 76.3 (C-5),
80.6 (C-4), 82.7 (C-3), 88.6 (C-2), 105.9 (C-1), 126.2–127.6 (C6H5),
137.7, 137.9, 138.3, 138.4 (Cipso). – C42H52O6 (652.87): calcd. C
77.27, H 8.03; found C 77.09, H 7.92.
Experimental Section
General: Dichloromethane, N,N-dimethylformamide (DMF) and
acetonitrile were dried over phosphorus pentoxide and distilled,
while diethyl ether was dried over sodium/benzophenone before
distilling. All other chemicals were commercially available and used
as received. Octyl β--galactofuranoside (1) was prepared accord-
Eur. J. Org. Chem. 2000, 1423Ϫ1431
1427

`
M. Gelin, V. Ferrieres, D. Plusquellec
FULL PAPER
1-O-Acetyl 2,3,5,6-Tetra-O-benzyl-
tion of 2 (2.00 g, 3.1 mmol) in dichloromethane (30 mL) were suc-
D
-galactofuranose (3): To a solu-
1 H, H-1), 7.27–7.50 (m, 5 H, C6H5). – 13C NMR: δ ϭ 20.7, 20.8,
21.0 (CH3CO), 62.5 (C-6), 69.0 (C-5), 76.5 (C-3), 79.6 (C-4), 81.2
cessively added at room temp. acetic anhydride (1.15 mL, (C-2), 90.4 (C-1), 127.9, 129.0, 132.2 (C6H5), 133.1 (Cipso), 169.6,
12.4 mmol) and sulfuric acid (66 µL, 1.2 mmol). After stirring for 169.9, 170.0, 170.5 (CO). – C20H24O9S (440.47): calcd. C 54.55, H
24 h, the reaction medium was neutralized with NaHCO3, filtered 5.47; found C 54.49, H 5.53.
and concentrated under reduced pressure. Purification by flash
Ethyl 2,3,5,6-Tetra-O-acetyl-1-thio-β-D-galactofuranoside (7β): Syn-
chromatography (light petroleum/ethyl acetate, 87:13) yielded 3
thesis of 7β was performed according to the previous procedure
starting from 5[39] and ethanethiol (0.23 mL) within 1.5 h. Purifica-
tion yielded 0.56 g (55%) of 7β as a colorless oil. – TLC (light
petroleum/ethyl acetate, 7:3): Rf ϭ 0.4. – [α]D ϭ –98.4 (c ϭ 1.01,
CH2Cl2). – 1H NMR: δ ϭ 1.28 (t, 3J ϭ 7.1 Hz, 3 H, CH3CH2),
(1.46 g, 81%, α/β ϭ 1:4.9) as a colorless oil. – TLC (light petroleum/
ethyl acetate, 4:1): Rf ϭ 0.37. – C36H38O7 (582.70): calcd. C 74.21,
H 6.57; found C 74.31, H 6.62.
3α: 1H NMR: δ ϭ 2.07 (s, 3 H, CH3CO), 3.61–3.65 (m, 2 H, H-6),
4.18 (dd, J3,4 ϭ 7.7 Hz, J4,5 ϭ 4.2 Hz, 1 H, H-4), 4.30–4.74 (m, 8
H, CH2Ph), 6.22 (d, J1,2 ϭ 4.2 Hz, 1 H, H-1), 7.18–7.37 (m, 20 H,
C6H5). – 13C NMR: δ ϭ 21.2 (CH3CO), 70.2 (C-6), 72.4, 73.0,
73.1, 73.4 (CH2Ph), 77.6 (C-5), 79.5 (C-4), 81.3 (C-3), 83.6 (C-2),
93.7 (C-1), 127.5–128.5 (C6H5), 137.2–138.5 (Cipso), 170.2 (CO).
2
2.04, 2.08, 2.09, 2.11 (4 s, 12 H, CH3CO), 2.62 (dq, J ϭ 12.7 Hz,
2
1 H, CH3CH2), 2.69 (dq, J ϭ 12.7 Hz, 1 H, CH3CH2), 4.18 (dd,
J6a,6b ϭ 11.8 Hz, J5,6a ϭ 7.2 Hz, 1 H, H-6a), 4.31 (dd, J5,6b
ϭ
4.6 Hz, 1 H, H-6b), 4.38 (dd, J3,4 ϭ 6.1 Hz, J4,5 ϭ 3.6 Hz, 1 H, H-
4), 5.02 (dd, J2,3 ϭ 2.0 Hz, 1 H, H-3), 5.06 (br. t, J ϭ 2.4 Hz, 1 H,
H-2), 5.32 (d, J1,2 ϭ 2.0 Hz, 1 H, H-1), 5.39 (ddd, 1 H, H-5). – 13
C
1
3β: H NMR: δ ϭ 2.07 (s, 3 H, CH3CO), 3.67 (d, J5,6 ϭ 5.5 Hz, 2
NMR: δ ϭ 14.8 (CH3CH2), 20.6, 20.7, 20.8, 20.9 (CH3CO), 25.3
(CH3CH2), 62.5 (C-6), 69.0 (C-5), 76.7 (C-3), 79.2 (C-4), 81.7 (C-
2), 87.6 (C-1), 169.7, 169.9, 170.0, 170.4 (CO). – C16H24O9S
(392.43): calcd. C 48.97, H 6.16; found C 48.92, H 6.14.
H, H-6), 3.79 (dd, 1 H, J4,5 ϭ 4.4 Hz, 1 H, H-5), 4.02 (d, J2,3
ϭ
1.8 Hz, 1 H, H-2), 4.05 (dd, J3,4 ϭ 6.1 Hz, 1 H, H-3), 4.29 (dd, 1
H, H-4), 4.30–4.74 (m, 8 H, CH2Ph), 6.25 (s, 1 H, H-1), 7.18–7.37
(m, 20 H, C6H5). – 13C NMR: δ ϭ 21.3 (CH3CO), 70.6 (C-6), 71.8,
72.1, 73.2, 73.4 (CH2Ph), 76.5 (C-5), 83.0 (C-4), 84.0 (C-3), 87.1
(C-2), 100.4 (C-1), 127.5–128.2 (C6H5), 137.2–138.5 (Cipso), 170.0
(CO).
Phenyl 2,3,5,6-Tetra-O-acetyl-1-thio-D-glucofuranoside (10): Syn-
thesis of 10 was performed according to the previous procedure
starting from 9[39] and thiophenol (0.32 mL) within 5 h. Purifica-
tion yielded 0.80 g (70%) of an anomeric mixture of 10 (α/β ϭ
1:9). – TLC (light petroleum/ethyl acetate, 3:2): Rf ϭ 0.45. –
C20H24O9S (440.47): calcd. C 54.55, H 5.47; found C 54.72, H 5.51.
Phenyl 2,3,5,6-Tetra-O-benzyl-1-thio-D-galactofuranoside (4): To a
cooled (0 °C) solution of 3 (1.50 g, 2.6 mmol) in dry dichlorome-
thane (15 mL) were successively added thiophenol (0.32 mL,
3.1 mmol) and BF3 OEt2 (0.65 mL, 5.1 mmol). After stirring at 0
°C for 1 h, the reaction medium was diluted with dichloromethane
(40 mL), washed with 5% aq. NaHCO3 (4 ϫ 10 mL), dried
(MgSO4) and concentrated under reduced pressure. Purification of
the residue by flash-chromatography (light petroleum/diethyl ether,
9:1) gave an anomeric mixture of 4 (0.65 g, 40%, α/β ϭ 1:1). – TLC
(light petroleum/ethyl acetate, 9:1): Rf ϭ 0.3. – For characterization
10β: 1H NMR: δ ϭ 2.01, 2.06, 2.09, 2.12 (4 s, 12 H, CH3CO), 4.18
(dd, J6a,6b ϭ 12.3 Hz, J5,6a ϭ 4.8 Hz, 1 H, H-6a), 4.41 (dd, J3,4
ϭ
4.2 Hz, J4,5 ϭ 9.3 Hz, 1 H, H-4), 4.63 (dd, J5,6b ϭ 2.4 Hz, 1 H, H-
6b), 5.19 (dd, J1,2 ϭ 2.0 Hz, J2,3 ϭ 1.0 Hz, 1 H, H-2), 5.32 (d, 1 H,
H-1), 5.35 (ddd, 1 H, H-5), 5.37 (d, 1 H, H-3), 7.27–7.53 (m, 5 H,
C6H5). – 13C NMR: δ ϭ 20.7, 20.8 (CH3CO), 63.1 (C-6), 68.1 (C-
5), 74.0 (C-3), 78.9 (C-4), 81.2 (C-2), 91.1 (C-1), 127.9, 129.1
(C6H5), 132.3 (Cipso), 169.1 169.3, 169.6, 170.6 (CO).
1
of 4β, see above. – Selected data for the α anomer: H NMR: δ ϭ
3.55 (dd, J6a,6b ϭ 10.6 Hz, J5,6a ϭ 6.1 Hz, 1 H, H-6a), 3.65 (dd,
J5,6b ϭ 4.6 Hz, 1 H, H-6b), 3.95 (ddd, J4,5 ϭ 7.1 Hz, 1 H, H-5),
4.13 (dd, J3,4 ϭ 4.6 Hz, 1 H, H-4), 4.22 (t, J2,3 ϭ 4.6 Hz, 1 H, H-
3), 4.26 (t, J1,2 ϭ 4.6 Hz, 1 H, H-2), 4.41–4.76 (m, 8 H, CH2Ph),
5.69 (d, 1 H, H-1), 7.19–7.55 (m, 20 H, C6H5). – 13C NMR: δ ϭ
70.7 (C-6), 71.8, 72.4, 73.3, 73.4 (CH2Ph), 78.5 (C-5), 81.9 (C-3),
84.1 (C-4), 84.3 (C-2), 89.4 (C-1), 126.6–130.6 (C6H5), 135.6, 137.3,
1
10α: selected data H NMR: δ ϭ 2.02–2.11 (4 s, 12 H, CH3CO),
4.17 (dd, J6a,6b ϭ 12.3 Hz, J5,6a ϭ 5.2 Hz, 1 H, H-6a), 4.55 (dd,
J5,6b ϭ 2.4 Hz, 1 H, H-6b), 4.59 (dd, J4,5 ϭ 9.4 Hz, J3,4 ϭ 3.9 Hz,
1 H, H-4), 5.24 (ddd, 1 H, H-5), 5.43 (dd, J1,2 ϭ 5.2 Hz, J2,3
1.5 Hz, 1 H, H-2), 5.47 (dd, 1 H, H-3), 5.80 (d, 1 H, H-1), 7.27–
7.53 (m, 5 H, C6H5). – 13C NMR: δ ϭ 20.0–20.6 (CH3CO), 63.1
(C-6), 67.5 (C-5), 74.7 (C-4), 75.9 (C-3), 77.7 (C-2), 90.3 (C-1),
132.0, 128.8 (C6H5), 133.6 (Cipso), 169.1–170.6 (CO).
ϭ
137.7, 138.2, 138.8 (Cipso)
.
General Procedure for the Synthesis of Per-O-acetylated Thioglyco-
furanosides (6β, 7β, 10, 13): To a cooled (0 °C) solution of the
appropriate penta-O-acetyl-hexofuranose[39] (1.00 g, 2.6 mmol) in
dry dichloromethane (30 mL) were successively added at 0 °C the
thiol (3.1 mmol) and BF3 OEt2 (0.98 mL, 7.8 mmol). After stirring
at 0 °C for 1.5–5 h, workup and purification [flash-chromatography
(light petroleum/ethyl acetate, 3:1)] were then similar to that de-
scribed for compound 4.
Phenyl 2,3,5,6-Tetra-O-acetyl-1-thio-D-mannofuranoside (13): Syn-
thesis of 13 was performed according to the previous procedure
starting from 12[39] and thiophenol (0.32 mL) within 4.25 h. Puri-
fication yielded 1.03 g (90%) of an anomeric mixture of 13 (α/β ϭ
15.7:1). – TLC (light petroleum/ethyl acetate, 3:2): Rf ϭ 0.44. –
C20H24O9S (440.47): calcd. C 54.55, H 5.47; found C 54.58, H 5.49.
1
13α: H NMR: δ ϭ 1.99, 2.07, 2.08 (4 s, 12 H, CH3CO), 4,15 (dd,
J6a,6b ϭ 12.3 Hz, J5,6a ϭ 5.1 Hz, 1 H, H-6a), 4.33 (dd, J5,4
Phenyl 2,3,5,6-Tetra-O-acetyl-1-thio-β-D-galactofuranoside (6β):
ϭ
Synthesis of 6β was performed according to the previous procedure
starting from 5[39] and thiophenol (0.32 mL) within 3 h. Purifica-
tion yielded 0.93 g (81%) of 6β as a colorless oil. – TLC (light
petroleum/ethyl acetate, 7:3): Rf ϭ 0.3. – [α]D ϭ –105.9 (c ϭ 1.01,
CH2Cl2). – 1H NMR: δ ϭ 2.04, 2.09, 2.11, 2.13 (4 s, 12 H,
CH3CO), 4.18 (dd, J6a,6b ϭ 11.8 Hz, J5,6a ϭ 7.1 Hz, 1 H, H-6a),
4.33 (dd, J5,6b ϭ 4.6 Hz, 1 H, H-6b), 4.48 (dd, J3,4 ϭ 6.0 Hz, J4,5 ϭ
9.3 Hz, J3,4 ϭ 3.2 Hz, 1 H, H-4), 4.55 (dd, J5,6b ϭ 2.3 Hz, 1 H, H-
6b), 5.25 (dd, J1,2 ϭ 7.1 Hz, J2,3 ϭ 4.6 Hz, 1 H, H-2), 5.28 (ddd, 1
H, H-5), 5.40 (d, 1 H, H-1), 5.48 (dd, 1 H, H-3), 7.32–7.52 (m, 5
H, C6H5). – 13C NMR: δ ϭ 20.4, 20.7 (CH3CO), 62.7 (C-6), 67.6
(C-5), 70.2 (C-3), 74.6 (C-2), 76.3 (C-4), 87.5 (C-1), 128.3, 129.0
(C6H5), 133.0 (Cipso), 169.3, 169.6, 170.6 (CO).
1
3.8 Hz, 1 H, H-4), 5.08 (dd, J2,3 ϭ 2.6 Hz, 1 H, H-3), 5.23 (t, J1,2
ഠ
13β: selected data H NMR: δ ϭ 2.02, 2.15 (4 s, 12 H, CH3CO),
J2,3 ϭ 2.5 Hz, 1 H, H-2), 5.40 (dt, J ϭ 4.2 Hz, 1 H, H-5), 5.51 (d, 4.20 (dd, J6a,6b ϭ 12.4 Hz, J5,6a ϭ 4.6 Hz, 1 H, H-6a), 4.36 (dd,
1428 Eur. J. Org. Chem. 2000, 1423Ϫ1431

A General and Diastereoselective Synthesis of 1,2-cis-Hexofuranosides
J4,5 ϭ 9.5 Hz, J3,4 ϭ 4.4 Hz, 1 H, H-4), 4.63 (dd, J5,6b ϭ 2.4 Hz, 1
FULL PAPER
Phenyl 2,3,5,6-Tetra-O-benzyl-1-thio-α-
D-mannofuranoside (14α):
H, H-6b), 5.41 (dd, J1,2 ϭ 6.8 Hz, J2,3 ϭ 4.8 Hz, 1 H, H-2), 5.46– Compound 14α was obtained from 7 (0.50 g) according to the pre-
5.49 (m, 1 H, H-5), 5.65 (br. t, J ϭ 4.6 Hz,1 H, H-3), 5.79 (d, 1 H, vious procedure as a colorless solid in 73% yield (0.51 g) which
H-1), 7.23–7.48 (m, 5 H, C6H5). – 13C NMR: δ ϭ 20.5, 20.6, 20.8 was recrystallized from light petroleum/diethyl ether. – TLC (light
(CH3CO), 62.7 (C-6), 68.5 (C-5), 69.5 (C-3), 72.1 (C-2), 76.0 (C-4),
petroleum/ethyl acetate, 9:1): Rf ϭ 0.33. – m.p. 84–86 °C. – [α]D
ϭ
89.9 (C-1), 127.5, 131.7 (C6H5), 132.0 (Cipso), 169.5, 169.6, 169.7, ϩ64.0 (c ϭ 1.00, CH2Cl2). – 1H NMR: δ ϭ 3.64 (dd, J6a,6b
ϭ
170.6 (CO).
10.7 Hz, J5,6a ϭ 4.7 Hz, 1 H, H-6a), 3.86 (dd, J5,6b ϭ 1.8 Hz, 1 H,
H-6b), 3.97 (dd, J1,2 ϭ 7.2 Hz, J2,3 ϭ 4.1 Hz, 1 H, H-2), 4.05 (ddd,
J4,5 ϭ 8.8 Hz, 1 H, H-5), 4.11 (dd, J3,4 ϭ 2.6 Hz, 1 H, H-4), 4.13
(dd, 1 H, H-3), 4.42–4.91 (m, 8 H, CH2Ph), 5.49 (d, 1 H, H-1),
7.20–7.45 (m, 25 H, C6H5). – 13C NMR: δ ϭ 70.0 (C-6), 72.2, 73.1,
73.6, 73.9 (CH2Ph), 75.9 (C-5), 77.5 (C-3), 78.7 (C-4), 84.1 (C-2),
88.5 (C-1), 127.5–132.3 (C6H5), 134.0, 137.6, 138.5, 138.6, 138.8
(Cipso). – C40H40O5S (632.82): calcd. C 75.94, H 6.34; found C
75.91, H 6.31.
General Procedure for the Synthesis of Per-O-benzylated Thioglyco-
furanosides (4β, 8β, 11β, 14α): To a solution of the appropriate
tetra-O-acetyl-1-thio--hexofuranoside (1.1 mmol) in methanol
(5 mL) was added a 0.1  solution of sodium methylate in meth-
anol (9 mL, 0.9 mmol). After stirring at room temp. for 10 min, the
reaction was neutralized with IR-120 Hϩ-form resin, filtered and
concentrated under reduced pressure. The resulting residue was
then diluted with DMF (12 mL). To this solution cooled at 0 °C
were successively added a 60% dispersion of sodium hydride in
mineral oil (0.22 g, 5.4 mmol) and benzyl bromide (0.65 mL,
5.4 mmol). The reaction was allowed to stir at room temp. for 2 h,
methanol added (10 mL) and concentrated under reduced pressure
at 50 °C. Flash chromatography (light petroleum/ethyl acetate, 9:1)
yielded the required 1,2-trans thioglycofuranoside.
General Procedure for the Synthesis of 1,2-cis-Hexofuranosides: A
solution of hexofuranosyl donor (0.10 g, 0.16 mmol) and glycosyl
acceptor (0.13 mmol) in dichloromethane (1 mL) was stirred to-
˚
gether with 4 A molecular sieves (100 mg) at room temp. for
10 min. To the solution placed in the dark and cooled at 0 °C were
successively added N-iodosuccinimide (0.036 g, 0.16 mmol) and
tin(II) triflate (5.0 mg, 0.01 mmol). The reaction was monitored by
TLC and quenched with triethylamine after total disappearance of
the acceptor. The resulting solution was filtered over a bed of celite,
concentrated and purified by flash-chromatography.
Phenyl 2,3,5,6-Tetra-O-benzyl-1-thio-β-D-galactofuranoside (4β):
Compound 4β was obtained from 6β (0.50 g) according to the pre-
vious procedure as a colorless oil in 80% yield (0.56 g). – TLC (light
petroleum/ethyl acetate, 9:1): Rf ϭ 0.3. – [α]D ϭ –121.4 (c ϭ 1.54,
CH2Cl2). – 1H NMR: δ ϭ 3.65 (dd, J6a,6b ϭ 10.0 Hz, J5,6a
ϭ
Methyl 2,3,5,6-Tetra-O-benzyl-D-glucofuranosyl-(1Ǟ6)-2,3,4-tri-O-
5.4 Hz, 1 H, H-6a), 3.71 (dd, J5,6b ϭ 6.4 Hz, 1 H, H-6b), 3.82 (ddd,
J4,5 ϭ 3.2 Hz, 1 H, H-5), 4.08 (dd, J2,3 ϭ 3.0 Hz, J1,2 ϭ 2.4 Hz, 1
H, H-2), 4.09 (dd, J3,4 ϭ 6.7 Hz, 1 H, H-3), 4.28–4.71 (m, 8 H,
CH2Ph), 4.36 (dd, 1 H, H-4), 5.61 (d, 1 H, H-1), 7.20–7.48 (m, 25
H, C6H5). – 13C NMR: δ ϭ 70.6 (C-6), 72.0, 72.1, 73.2, 73.4
(CH2Ph), 76.1 (C-5), 80.5 (C-4), 82.7 (C-3), 88.6 (C-2), 89.9 (C-
1), 127.0–131.2 (C6H5), 134.7, 137.3, 137.6, 138.2, 138.3 (Cipso). –
C40H40O5S (632.82): calcd. C 75.94, H 6.34; found C 75.69, H 6.51.
acetyl-α- -glucopyranoside (15a): The synthesis of 15a was per-
D
formed starting from 11β and acceptor A (0.042 g) for 10 min.
Chromatographic purification (light petroleum/ethyl acetate, 3:1)
gave an anomeric mixture of the desired disaccharide (0.093 g, α/
β ϭ 5.7:1) in 84% yield. – TLC (light petroleum/ethyl acetate, 7:3):
Rf ϭ 0.23. – C47H54O14 (842.94): calcd. C 66.97, H 6.46; found C
66.69, H 6.56.
2,3,5,6-Tetra-O-benzyl-
D-glucofuranosyl-(1Ǟ6)-1,2:3,4-di-O-iso-
Ethyl 2,3,5,6-Tetra-O-benzyl-1-thio-β-D-galactofuranoside (8β):
propylidene-α- -galactopyranose (15b): The synthesis of 15b was
D
Compound 8β was obtained from 7β (0.45 g) according to the pre-
vious procedure as a colorless oil in 74% yield (0.48 g). – TLC (light
petroleum/ethyl acetate, 9:1): Rf ϭ 0.52. – [α]D ϭ –99.5 (c ϭ 1.0,
CH2Cl2). – 1H NMR: δ ϭ 1.27 (t, 3J ϭ 7.4 Hz, 3 H, CH2CH3),
performed starting from 11β and acceptor B (0.034 g) for 10 min
and yielded 0.082 g (87%, α/β ϭ 4.6:1) of the required disaccharide.
The major anomer could be chromatographically isolated (light
petroleum/ethyl acetate, 17:3) as a colorless oil. – 15bα: TLC (light
petroleum/ethyl acetate, 7:3): Rf ϭ 0.56. – [α]D ϭ ϩ14.5 (c ϭ 0.88,
CH2Cl2). – C46H54O11 (782.93): calcd. C 70.57, H 6.95; found C
70.35, H 6.91.
2
2.58 (dq, J ϭ 13.0 Hz, 1 H, CH2CH3), 2.68 (dq, 1 H, CH2CH3),
3.66 (dd, J6a,6b ϭ 9.9 Hz, J5,6a ϭ 5.1 Hz, 1 H, H-6a), 3.72 (dd,
J5,6b ϭ 6.5 Hz, 1 H, H-6b), 3.81 (ddd, J4,5 ϭ 3.1 Hz, 1 H, H-5),
3.93 (br. t, J ϭ 2.9 Hz, 1 H, H-2), 4.04 (dd, J3,4 ϭ 7.4 Hz, J2,3
3.2 Hz, 1 H, H-3), 4.25 (dd, 1 H, H-4), 4.26–4.73 (m, 8 H, CH2Ph),
5.40 (d, J1,2 ϭ 2.7 Hz, 1 H, H-1), 7.19–7.34 (m, 25 H, C6H5). – 13
ϭ
Methyl 2,3,5,6-Tetra-O-benzyl-
D-glucofuranosyl-(1Ǟ4)-2,3,6-tri-O-
C
benzyl-α- -glucopyranoside (15c): The synthesis of 15c was per-
D
NMR: δ ϭ 15.0 (CH2CH3), 25.2 (CH2CH3), 71.0 (C-6), 71.8, 72.1,
73.3, 73.4 (CH2Ph), 76.1 (C-5), 80.2 (C-4), 82.9 (C-3), 87.0 (C-2),
88.9 (C-1), 127.5–128.4 (C6H5), 137.5, 137.7, 138.2, 138.3 (Cipso). –
C36H40O5S (584.78): C 73.97, H 6.86; found C 73.98, H 6.89.
formed starting from 11β and acceptor C (0.061 g) for 7 min and
yielded 0.088 g (68% α/β ϭ 2.1:1) of the required disaccharide after
chromatographic purification (light petroleum/ethyl acetate,
17:3). – TLC (light petroleum/ethyl acetate, 7:3): Rf ϭ 0.55. –
C62H66O11 (987.21): calcd. C 75.43, H 6.74; found C 75.46, H 6.78.
Phenyl 2,3,5,6-Tetra-O-benzyl-1-thio-β-D-glucofuranoside (11β):
Compound 11β was obtained from 6 (0.50 g) according to the pre-
vious procedure as a colorless oil in 81% yield (0.56 g). – TLC (light
petroleum/ethyl acetate, 9:1): Rf ϭ 0.33. – [α]D ϭ –92.5 (c ϭ 0.94,
Methyl 2,3,5,6-Tetra-O-benzyl-
D-galactofuranosyl-(1Ǟ6)-2,3,4-tri-
O-acetyl-α- -glucopyranoside (16a): The synthesis of 16a was per-
D
formed starting from 4β and acceptor A (0.048 g) for 10 min. Chro-
matographic purification gave an anomeric mixture of the desired
disaccharide (0.090 g, 84%, α/β ϭ 5.3:1). – TLC (light petroleum/
ethyl acetate, 3:2): Rf ϭ 0.53. – C47H54O14 (842.94): calcd. C 66.97,
H 6.46; found C 67.01, H 6.57.
CH2Cl2). – 1H NMR: δ ϭ 3.71 (dd, J6a,6b ϭ 10.7 Hz, J5,6a
ϭ
5.1 Hz, 1 H, H-6a), 3.89 (dd, J5,6b ϭ 2.0 Hz, 1 H, H-6b), 4.12–4.14
(m, 2 H, H-2, H-3), 4.16 (ddd, J4,5 ϭ 9.2 Hz, 1 H, H-5), 4.34 (dd,
J
3,4 ϭ 3.8 Hz, 1 H, H-4), 4.42–4.77 (m, 8 H, CH2Ph), 5.39 (d, J1,2 ϭ
1.9 Hz, 1 H, H-1), 7.19–7.45 (m, 25 H, C6H5). – 13C NMR: δ ϭ
70.6 (C-6), 71.8, 71.9, 72.4, 73.3 (CH2Ph), 76.1 (C-5), 81.2 (C-3), 2,3,5,6-Tetra-O-benzyl-
D
-galactofuranosyl-(1Ǟ6)-1,2:3,4-di-O-iso-
81.3 (C-4), 86.4 (C-2), 90.5 (C-1), 126.7–130.6 (C6H5), 135.8, 137.2,
137.6, 138.6, 138.8 (Cipso). – C40H40O5S (632.82): calcd. C 75.94, H
6.34; found C 75.85, H 6.33.
propylidene-α-D-galactopyranose (16b): The synthesis of 16b was
performed starting from 4β and acceptor B (0.034 g) for 20 min.
Purification gave an anomeric mixture of the desired disaccharide
Eur. J. Org. Chem. 2000, 1423Ϫ1431
1429

`
M. Gelin, V. Ferrieres, D. Plusquellec
FULL PAPER
Thomas-Oates, A. Dell, A. Bacic, J. Biol. Chem. 1990, 265,
(0.082 g, 81%, α/β ϭ 3.3:1). – TLC (light petroleum/ethyl acetate,
7:3): Rf ϭ 0.57. – C46H54O11 (782.93): calcd. C 70.57, H 6.95; found
C 70.19, H 7.08.
7385–7394.
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O-benzyl-α- -glucopyranoside (16c): The synthesis of 16c was per-
D
formed starting from 4β and acceptor C (0.061 g) for 12 min and
yielded 0.108 g (83%, α/β ϭ 1.7:1) of the required disaccharide. The
major anomer could be chromatographically isolated (light petro-
leum/ethyl acetate, 7:3) as a colorless oil.
[10]
[11]
[12]
16cα: TLC (light petroleum/ethyl acetate, 7:3): Rf ϭ 0.65. – [α]D
ϭ
ϩ51.0 (c ϭ 0.87, CH2Cl2). – C62H66O11 (987.21): calcd. C 75.43,
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ϭ
ϩ18.2 (c ϭ 1.00, CH2Cl2). – C62H66O11 (987.21): calcd. C 75.43,
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gave an anomeric mixture of the required disaccharide (0.099 g,
90%, α/β ϭ 1:3.3) as a colorless oil. – TLC (light petroleum/ethyl
acetate, 7:3): Rf ϭ 0.28. – C47H54O14 (842.94): calcd. C 66.97, H
6.46; found C 66.71, H 6.60.
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2,3,5,6-Tetra-O-benzyl-
D-mannofuranosyl-(1Ǟ6)-1,2:3,4-di-O-iso-
propylidene-α- -galactopyranose (17b): The synthesis of 17b was
D
performed starting from 14α and acceptor B (0.034 g) for 12 min
and yielded 0.088 g (87%, α/β ϭ 1:2.3) of the desired disaccharide.
Chromatographic purification (light petroleum/ethyl acetate, 17:3)
gave the major β-anomer as a colorless oil. – 17bα: TLC (light
petroleum/ethyl acetate, 7:3): Rf ϭ 0.64. – 17bβ: TLC (light petro-
leum/ethyl acetate, 7:3): Rf ϭ 0.58. – [α]D ϭ –88 (c ϭ 0.47,
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´
´ ´
P. Fügedi, A. Liptak, P. Nanasi, Carbohydr. Res. 1982, 107,
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M. Gelin, V. Ferrieres, D. Plusquellec, Carbohydr. Lett. 1997,
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major β-mannofuranoside could be chromatographically isolated
(light petroleum/ethyl acetate, 17:3) as a colorless oil. – 17cα: TLC
(light petroleum/ethyl acetate, 7:3): Rf ϭ 0.61. – 17cβ: TLC (light
petroleum/ethyl acetate, 7:3): Rf ϭ 0.58. – C62H66O11, H2O
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Even if these compounds have the potential to form five-, six-
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Acknowledgments
We are grateful to M. Lefeuvre for helpful assistance in NMR ex-
`
periments, to the Ministere de l’Education Nationale, de l’Enseig-
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´
nement Superieur et de la Recherche (MENRT) for a grant to M.
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Eur. J. Org. Chem. 2000, 1423Ϫ1431

A General and Diastereoselective Synthesis of 1,2-cis-Hexofuranosides
FULL PAPER
R. R. Schmidt in Comprehensive Organic Synthesis, Pergamon
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Eur. J. Org. Chem. 2000, 1423Ϫ1431
1431