Evidence for endocyclic cleavage of conformationally restricted glycopyranosides

Article abstract of DOI:10.1002/chem.200900064

2,3-trans-carbamate- and -carbonate-carrying pyranosides were very easily anomerised from the ss to the a direction in the presence of a Lewis acid compared to other pyranosides. This reaction is caused by endocyclic cleavage of the pyranosides. Evidence

Full text of DOI:10.1002/chem.200900064

DOI: 10.1002/chem.200900064
Evidence for Endocyclic Cleavage of Conformationally Restricted
Glycopyranosides
AHCTUNGTRENNUNG
Shino Manabe,*[a, b] Kazuyuki Ishii,[a, b] Daisuke Hashizume,[c] Hiroyuki Koshino,[c] and
Yukishige Ito*[a]
Abstract: 2,3-trans-carbamate- and -carbonate-carrying pyranosides were very
easily anomerised from the b to the a direction in the presence of a Lewis acid
compared to other pyranosides. This reaction is caused by endocyclic cleavage of
Keywords: carbohydrates · cations ·
the pyranosides. Evidence for endocyclic cleavage of conformationally restricted
cleavage reactions · Friedel–Crafts
pyranosides in the chair form was obtained by intra- and intermolecular Friedel–
reaction · reduction
Crafts reactions, chloride addition, and reduction of the generated cation. On the
other hand, pyranosides with the distorted conformation were never cleaved in an
endocyclic manner.
Introduction
oxygen atom breaks to give the cyclic oxocarbonium ion.
This type of cleavage is a well-accepted mechanism, the im-
portance of which has been clearly seen in the great success
of oligosaccharide synthesis.[2] The second is endocyclic
cleavage, in which the bond between the anomeric carbon
atom and the pyranose-ring oxygen atom breaks. Although
both of these mechanisms have long been recognised as po-
tential cleavage pathways in acetals,[1] the endo cleavage
mode is not very common in carbohydrate chemistry.
The hydrolytic cleavage of glycosides has been extensively
studied because of its importance to carbohydrate chemistry,
biochemistry, and technology. Glycosides are unsymmetrical
acetals, so there are two pathways possible for their hydroly-
sis (Scheme 1).[1] The first is exocyclic cleavage, in which the
bond between the anomeric carbon atom and the exocyclic
Haworth et al. reported as early as 1941 that 3,6-anhydro-
methylglucosides were hydrolysed in the endo mode.[3] En-
docyclic cleavage occurs more commonly in aldofurano-
sides,[4] but in the case of pyranosides, strong Lewis acids
such as SnCl4 and Me2BBr are needed in aprotic media.[5]
Post and Karplus hypothesised a mechanism for endo-mode
hydrolysis of oligosaccharides based on molecular dynamics
calculations on lysozyme, in which the conformation of the
N-acetylglucopyranoside was restricted to the chair form in
the enzyme.[6,7] Since then, several studies have reported on
the endo cleavage of pyranosides. For instance, Gupta and
Franck succeeded in capturing the cation generated by endo
cleavage through an intramolecular aza-Diels–Alder reac-
tion during cis-fused decalin pyranoside acetal methanoly-
sis.[8] Fraser-Reid and co-workers showed the presence of
linear acetylium ions in acetic acid during the acetolysis of
acyl-protected methylglycosides in the presence of ferric
chloride.[9] Anslyn and co-workers used a deuterium scram-
bling test to show that only the cis-decalin type of conforma-
tionally locked b-alkyl acetal underwent endocyclic cleav-
age, with a maximum 30% yield, in MeOH.[10]
Scheme 1. Endocyclic and exocyclic cleavage of glycosides.
[a] Dr. S. Manabe, Dr. K. Ishii, Dr. Y. Ito
RIKEN Advanced Science Institute
Wako, Hirosawa, Saitama 351-0198 (Japan)
Fax : (+81)48-462-4680
E-mail: smanabe@riken.jp
yukito@riken.jp
[b] Dr. S. Manabe, Dr. K. Ishii
PRESTO (Japan) Science and Technology Agency
Honcho, Kawaguchi, Saitama, 332-0012 (Japan)
[c] Dr. D. Hashizume, Dr. H. Koshino
Advanced Technology Support Division
RIKEN Advanced Science Institute
Wako, Hirosawa, Saitama 351-0198 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900064.
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FULL PAPER
Calculations by Karplus, Deslongchamps, and their re-
spective co-workers[6,11,12] indicated that a-glycosides must
be hydrolysed from their ground-state chair conformation
by exo cleavage, whereas b-glycosides must adopt a different
conformation prior to exo cleavage, in order to accommo-
date stereoelectronic factors. That is, exocyclic cleavage of b
anomers does not obey the theory of stereoelectronic con-
trol unless conformational changes are introduced into the
pyranose ring. The twist-boat or flattened-chair conforma-
tions could lead to stereoelectronically allowed exocyclic
cleavage of a b anomer.
(Q=0.6550(14) ꢁ, q=174.18(12)8, and f=275.6(12)8) that
1 adopted the C1 chair conformation (Figure 1). Similarly,
4
X-ray crystallography revealed that the glycosides 3 and 4
4
adopted the C1 chair conformation.[15,17] The NMR coupling
Pyranosides with 2,3-trans-oxazolidinone groups were
quite easily anomerised from the b to the a direction by
weak Lewis acids and Brønsted acids compared to typical
pyranosides, as found by us and independently by Crich
et al.[13,14] Very recently, Oscarson and co-workers have re-
ported the anomerisation of a disaccharide carrying a 2,3-
trans-oxazolidinone and suggested the possibility of endo
cleavage.[15] Although an attempt at capture of the inter-
mediate cation was not successful, the anomerisation reac-
tion was observed in the presence of excess MeOH without
transacetalisation of the glycosidic bond in their case. We
speculated that 2,3-trans-carbamate or -carbonate groups
would help lock the pyranoside ring conformation strictly in
Figure 1. A view of the molecular structure of 1, illustrating the atom-la-
belling scheme. Displacement ellipsoids are drawn at the 50% probabili-
ty level.
constants of compounds 1–4 were also typical of the chair
conformation. In contrast, the mannopyranoside 5 with a
cis-fused 2,3-carbonate group was distorted from the chair
conformation[18] and instead adopted an E2-oriented 4C1 con-
formation. The rhamnoside and daunosamides with cis-2,3-
carbonate groups also had distorted pyranosides.[19,20] From
these results, the trans-carbamate- or -carbonate-carrying
4
a C1 chair form and that such conformationally locked pyr-
anosides would be cleaved in the endo mode. We report
here supporting evidence for endo cleavage of conforma-
tionally restricted pyranosides with 2,3-trans-carbamate and
-carbonate groups.
4
pyranosides had a C1 chair conformation, whereas the cis-
2,3-carbonate-carrying pyranosides had a distorted confor-
mation.
Results and Discussion
From the reductive benzylidene acetal cleavage reaction
of compound 2 with Et3SiH in the presence of BF3·OEt2 at
48C, the anomerised a-glycoside 7 was obtained in 24%
yield, together with b-glycoside 6 in 11% yield (Scheme 3).
Interestingly, the ring-opened product 8 was also obtained
in 38% yield. A mechanism for this reaction is proposed in
Scheme 4. After pyranose A is cleaved by acid in the endo
Our investigation commenced with a conformation study of
pyranosides carrying 2,3-trans-carbonate and -carbamate
groups. The conformations of pyranosides 1 and 3, carrying
2,3-trans-carbonates, and of pyranoside 4, carrying a 2,3-
trans-carbamate, were investigated by X-ray crystallography
(see the Supporting Information, Scheme 2). It appeared
clear from the torsion angles (O1-C1-C2-C3 64.83(12), C1-
C2-C3-C4 70.03(13), C2-C3-C4-C5 61.54(12), C3-C4-C5-O1
60.69(12), C4-C5-O1-C1 63.31(13), and C5-O1-C1-C2
60.63(13)8) and the Cremer–Pople puckering parameters[16]
ꢀ
mode, the C1 C2 bond rotates and pyranoside C recyclises
to the more thermodynamically stable a anomer D. In the
presence of the reducing reagent, cations B and C were re-
duced to the ring-opened product E. The endo-cleavage ten-
dency was more pronounced for galactoside 3 under reduc-
tion conditions with NaBH3CN/HCl. Thus, after reductive
benzylidene acetal cleavage by NaBH3CN and HCl in tetra-
hydrofuran (THF) at 08C and subsequent acetylation, only
ring-opened product
(Scheme 5).
9 was obtained in 60% yield
The pyranoside without a 2,3-trans-oxazolidinone group,
10, was not anomerised under the same conditions and the
b-thioglycoside 11[21] was obtained in 86% yield (Scheme 6).
Dibenzyl-protected galactose derivative 12 gave com-
pounds 13 and 14, together with the starting material 12,
under the same conditions as those above (Scheme 7). Com-
pound 13 comes from reduction of the cation generated by
endocyclic cleavage. The chloride adduct 14 was obtained as
an inseparable mixture in 1:1 ratio in 36% yield. Compound
Scheme 2. The substrates for X-ray crystallography. Bn: benzyl.
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S. Manabe, Y. Ito et al.
under the same conditions. At
08C, the anomerisation of a
anomer 15 was observed. The
4:15 ratio was 11:76 after 1 h.
At room temperature, com-
pounds 16 and 17 were formed
in 41% yield in a 5:1 ratio, to-
gether with 8% of b product 4.
Scheme 3. Anomerisation and reduction of pyranoside 2 bearing a 2,3-trans-carbonate group.
Scheme 4. The mechanism of anomerisation and reduction.
Scheme 8. Comparison of the anomerisation reactions and intramolecular
Friedel–Crafts reactions of 2,3-trans-carbamate-carrying a- and b-pyrano-
sides 4 and 15.
Scheme 5. Reduction of galactoside 3 through endocyclic cleavage.
The intramolecular Friedel–Crafts reaction products 16 and
17 were additional evidence of endo cleavage. The stereo-
chemistry at the newly generated asymmetric carbon atom
(C1) of 16 and 17 was determined as the S configuration
1
from H NMR coupling constants and NOESY analysis for
H1 and H3.
In the case of dibenzyl-protected compound 18 and diace-
tyl-protected b-thioglycoside 20, there was less anomerisa-
tion than with the 4-acetyl substrate 4 (Scheme 9).
When the anomerisation reaction of the trans-carbonate-
bearing glucoside 22 was carried out in CH2Cl2, the anomer-
ised product 23 was obtained (Scheme 10). When glucoside
22 was treated with BF3·OEt2 in toluene at ꢀ308C for 12 h,
compound 24 was obtained in 45% yield, along with 43%
of the starting material 22, but no anomerised product 23
Scheme 6. Reduction of 10, a galactoside without a 2,3-trans-carbonate
moiety.
Scheme 7. Reduction of and chloride addition to galactoside 12.
14 was stable during silica gel column chromatography pu-
rification. Addition of chloride ions from HCl to cations B
and/or C gave compound 14.
Contrary to previous reports,[8,11] the a anomer 15 was
anomerised, although a higher temperature was required
than that for the b anomer 4 (Scheme 8). At ꢀ308C, a
anomer 15 was recovered in 87% yield with a trace amount
of b anomer 4. The b anomer 4 was anomerised at ꢀ308C
Scheme 9. Protecting-group effect on the anomerisation reaction.
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Endocyclic Cleavage of Glycopyranosides
FULL PAPER
cause the a-oxygen-stabilised
cation is less stable than the a-
sulfur-stabilised
cation
(Scheme 12).[25]
On the other hand, the cis-
carbonate mannoside 33 with
its distorted conformation was
not anomerised, even at 48C or
at room temperature for 3 h.
The b-thioglycoside 33 was re-
covered
quantitatively
(Scheme 13). After a prolonged
reaction period at room tem-
perature, the acetate group was
removed and some decomposi-
tion products were obtained.
Scheme 10. Friedel–Crafts reaction and ring opening of pyranosides 22 and 25. [a] The 25:26 ratio was deter-
mined by H NMR spectroscopy. [b] Only the S-configured compound was obtained.
1
was detected. The formation of 24 also constituted evidence
for the generation of the endo-cleaved cation. That is, the
endo-cleaved product was trapped by the solvent in a Frie-
del–Crafts reaction under acidic conditions. The stereochem-
istry at the newly formed asymmetric C1 atom of 24 was de-
termined to be the S configuration by NOESY data and J-
based configuration analysis.[22] The S configuration showed
Scheme 12. Anomerisation of O-glycoside 31.
that the toluene approached from the opposite side of
cation plane to the O5 oxygen atom of the pyranoside in
structure B in Scheme 4. Similarly, the benzyl-protected b-
thioglycoside 25[23] gave the anomerised a-thioglycoside 26
in 23% yield in CH2Cl2, but the toluene Friedel–Crafts
adduct 27 was obtained in 15% yield in toluene. In this
case, in addition to the Friedel–Crafts adduct with the S con-
figuration, the R product was also obtained in an insepara-
1
ble mixture. From H NMR integration, the S:R ratio was
Scheme 13. Anomerisation test for 33, a pyranoside with a cis-carbonate
determined as 77:23.
moiety.
The cation generated through the endocyclic cleavage re-
action of an O-glycoside was captured by reduction with
Et3SiH and BF3·OEt2. After the reductive benzylidene
acetal cleavage reaction of 28[24] at 08C for 12 h, the anomer-
ised a product 29 and reduced diol 30 were obtained in
44% and 21% yields, respectively (Scheme 11). The corre-
Conclusions
We have reported here that pyranosides having 2,3-trans-
carbonate and -carbamate groups quite easily undergo endo-
mode cleavage. These substrates were endo cleaved under
milder conditions—lower temperature and a weaker acidic
medium—than previously reported. Both a and b substrates
were cleaved in the endo mode. The cations generated by
endocyclic cleavage were captured by intra- and intermolec-
ular Friedel–Crafts reactions, chloride addition, and reduc-
tion, whereas the cis-carbonate-bearing pyranoside was
never cleaved in the endo mode. It was found to be quite
important to lock the pyranoside conformation in the chair
form for endocyclic cleavage. The phenomena reported here
are consistent with previous discussions based on stereoelec-
tronic effects. A calculation investigation is currently under
way.[26] Detailed results will be reported in due course.
Scheme 11. Capture of the cation generated by endocyclic cleavage of O-
glycoside 28.
sponding b product was not obtained. The O-glycoside 31
was also anomerised in the presence of BF3·OEt2 in toluene.
After 12 h, b anomer 31 was completely anomerised to the
a anomer 32 in 88% yield. However, the toluene Friedel–
Crafts adduct was not observed in this case, probably be-
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S. Manabe, Y. Ito et al.
Anomerisation and reduction of 2: BF3·OEt2 (0.3 mL, 2.40 mmol) was
added slowly to a solution of compound 2 (389 mg, 1.20 mmol) and
Et3SiH (2.3 mL, 14.4 mmol) in CH2Cl2 (12 mL) at 48C. The mixture was
stirred at 48C for 1 h, then sat. NaHCO3 was added. The aqueous layer
was extracted with CHCl3. The combined layers were washed with water
and brine. After drying of the extracts over Na2SO4, the solvent was
evaporated. The mixture was purified by silica gel column chromatogra-
phy to give b anomer 6 (44 mg, 11%), a anomer 7 (95 mg, 24%), and re-
duced product 8 (148 mg, 38%). Methyl 6-O-benzyl-2,3-carbonyl-1-thio-
b-d-glucopyranoside (6): [a]2D4 =ꢀ47.5 (c=1.40 in CHCl3); 1H NMR: d=
7.39–7.30 (m, 5H), 4.71 (d, J=9.6 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H), 4.56
(d, J=12.0 Hz, 1H), 4.25 (dd, J=11.6, 10.0 Hz, 1H), 4.13 (m, 1H), 4.02
(dd, J=11.6, 9.6 Hz, 1H), 3.85 (dd, J=10.4, 4.4 Hz, 1H), 3.73 (dd, J=
10.4, 6.0 Hz, 1H), 3.66–3.50 (m, 2H), 3.18 (d, J=4.0 Hz, 1H), 2.23 ppm
(s, 3H); 13C NMR: d=153.02, 137.03, 128.53, 128.08, 127.79, 84.54, 81.46,
79.27, 76.68, 73.87, 69.91, 69.58, 12.04 ppm; HRMS: calcd for
C15H18O6SNa [M+Na]+: 349.0716; found: 349.0713. Methyl 6-O-benzyl-
2,3-carbonyl-1-thio-a-d-glucopyranoside (7): [a]2D4 =111 (c=0.5 in
CHCl3); 1H NMR: d=7.39–7.30 (m, 5H), 5.40 (d, J=4.8 Hz, 1H), 4.64
(d, J=12.4 Hz, 1H), 4.47 (d, J=12.4 Hz, 1H), 4.45 (d, J=11.6 Hz, 1H),
4.34 (dd, J=11.6, 4.8 Hz, 1H), 4.08 (dd, J=12.0, 3.6 Hz, 1H), 3.98 (m,
1H), 3.82 (dd, J=10.8, 4.4 Hz, 1H), 3.64 (dd, J=10.8, 4.4 Hz, 1H), 2.88
(d, J=3.6 Hz, 1H), 2.88 ppm (s, 3H); 13C NMR: d=153.5, 137.1, 128.6,
128.1, 127.8, 82.6, 81.0, 76.6, 73.8, 71.9, 70.3, 68.9, 13.7 ppm; HRMS:
calcd for C15H18O6SNa [M+Na]+: 349.0716; found: 349.0723. Reduced
compound 8: m.p. 788C; [a]2D4 =ꢀ61 (c=0.66 in CHCl3); 1H NMR: d=
7.35–7.24 (m, 5H), 4.86 (m, 1H), 4.74 (m, 1H), 4.56 (s, 2H), 3.86 (m,
1H), 3.70–3.67 (m, 3H), 2.87 (dd, J=14.4, 4.8 Hz, 1H), 2.76 (dd, J=14.4,
7.2 Hz, 1H), 2.17 ppm (s, 3H); 13C NMR: d=154.1, 137.0, 128.5, 128.0,
127.8, 80.3, 77.2, 73.7, 72.6, 71.3, 69.7, 36.8, 16.6 ppm; elemental analysis:
calcd (%) for C15H20O6S: C 54.86, H 6.14; found: C 54.55, H 6.13.
Experimental Section
General procedures: 1H NMR spectra were taken with a JEOL EX-400
instrument as solutions in CDCl3 unless otherwise mentioned. Chemical
shifts are reported in ppm downfield from the signal for Me4Si. 13C NMR
spectra were taken in CDCl3 unless otherwise mentioned, and CDCl3
(d=77.0 ppm) was used as the internal standard. Optical rotations were
measured with a JASCO DIP-310 apparatus as solutions in CHCl3 at am-
bient temperature. All reactions sensitive to air or moisture were carried
out under a nitrogen atmosphere. All reagents were purchased from com-
mercial suppliers and used without further purification. Kanto silica gel
(spherical, neutral, 100–210 mm) was used for column chromatography.
Silica gel 60 F254 (Merck) was used for analytical and preparative thin-
layer chromatography. 2D NMR spectra (for 16, 17, and 24) including
DQF-COSY, NOESY, HSQC, and HMBC spectra were recorded on a
JEOL ECA-600 spectrometer at a 1H frequency of 600.17 MHz. Long-
range heteronuclear coupling constant values were measured by hetero-
(w1)-half-filtered TOCSY (HETLOC) or J–HMBC experiments. HRMS
was performed with Quadrupole-TOF (Applied Biosystems) or JMS-
SX102 (BE, JEOL) instruments.
Phenyl 4,6-O-benzylidene-2,3-carbonyl-1-thio-b-d-glucopyranoside (1):
Triphosgene (2.00 g, 6.73 mmol) was added in several portions to a solu-
tion of phenyl 4,6-O-benzylidene-1-thio-b-d-thioglucopyranoside (3.50 g,
9.72 mmol) in Et3N (5 mL, 35.87 mmol) and CH2Cl2 (30 mL) at 48C.
After 30 min, the mixture was diluted with CH2Cl2 and sat. NaHCO3 was
added. The aqueous layer was extracted with CH2Cl2. After drying of the
organic layers over Na2SO4, the solvent was evaporated. The residue was
recrystallised from EtOAc and hexane to give carbonate 1 (3.62 g, 96%):
m.p. 153–1558C; [a]2D4 =93.5 (c=0.75 in CHCl3); 1H NMR: d=7.56 (dd,
J=7.6, 1.6 Hz, 2H), 7.45–7.34 (m, 8H), 5.55 (s, 1H), 4.95 (d, J=10.0 Hz,
1H), 4.47 (t, J=10.0 Hz, 1H), 4.40 (dd, J=10.4, 4.8 Hz, 1H), 3.95 (t, J=
8.8 Hz, 1H), 3.91–3.84 (m, 2H), 3.61 ppm (m, 1H); 13C NMR: d=152.3,
135.9, 132.8, 129.4, 129.4, 129.2, 128.3, 126.0, 101.4, 83.7, 80.9, 78.3, 77.1,
72.8, 68.2 ppm; elemental analysis: calcd (%) for C20H18O6S: C 62.16, H
4.70; found: C 62.19, H 5.19.
Diacetate 9: 4.0m HCl dioxane solution was added to a solution of ben-
zylidene acetal 3 (1.61 g, 4.17 mmol) and NaBH3CN (4.50 g, 71.61 mmol)
in THF (50 mL) in the presence of methyl orange at 48C until the colour
of the mixture became deep red. After the mixture had been stirred at
48C for 30 min, brine and EtOAc were added. The aqueous layer was ex-
tracted with EtOAc. The combined layers were washed with brine. After
drying of the mixture over Na2SO4, the solvent was removed in vacuo.
The crude residue was purified roughly by silica gel column chromatogra-
phy (hexane:EtOAc 7:3!1:1). The diol was dissolved in pyridine
(20 mL), and Ac2O (15 mL) was added. After the mixture had been left
overnight, the volatile reagents were removed, and the residue was puri-
fied by silica gel column chromatography (hexane:EtOAc 7:3) to give the
Methyl 4,6-O-benzylidene-2,3-carbonyl-1-thio-b-d-glucopyranoside (2):
Triphosgene (0.65 g, 2.19 mmol) in CH2Cl2 (2.5 mL) was added to a sus-
pension
of
methyl
4,6-O-benzylidene-1-thio-b-d-glucopyranoside
(435 mg, 1.46 mmol) and Et3N (0.61 mL, 4.38 mmol) in CH2Cl2 (10 mL)
at 48C. After the mixture had been stirred at 48C for 1 h, it was poured
into sat. NaHCO3, and the aqueous layer was extracted with CHCl3. The
combined layers were washed with water and brine. After drying of the
extracts over Na2SO4, the solvent was evaporated. The crude residue was
recrystallised from EtOAc and hexane to give carbonate 2 (395 mg,
83%). After concentration of the mother liquid, the residue was purified
by silica gel column chromatography (hexane:EtOAc 2:1) to give addi-
tional carbonate 2 (34 mg, 7%): m.p. 1808C; [a]2D3 =ꢀ99 (c=0.67 in
CHCl3); 1H NMR: d=7.46–7.44 (m, 2H), 7.37–7.27 (m, 3H), 5.59 (s,
1H), 4.82 (d, J=10.0 Hz, 1H), 4.49 (t, J=10.8 Hz, 1H), 4.38 (dd, J=10.8,
4.8 Hz, 1H), 4.13–4.06 (m, 2H), 3.90 (t, J=10.4 Hz, 1H), 3.61 ppm (m,
1H); 13C NMR: d=152.3, 139.7, 136.0, 129.4, 128.3, 127.5, 126.0, 101.4,
82.8, 81.0, 78.6, 77.8, 77.2, 72.9, 72.0, 68.2, 12.4 ppm; HRMS: calcd for
C15H16O6SNa [M+Na]+: 347.0565; found: 347.0577.
acetate (1.19 g, 60%) as
a
colourless oil: [a]2D4 =ꢀ41.6 (c=0.86 in
CHCl3); 1H NMR: d=7.37–7.21 (m, 10H), 5.43 (t, J=5.2 Hz, 1H), 5.11
(m, 1H), 4.60 (m, 1H), 4.58 (t, J=4.8 Hz, 1H), 4.45 (d, J=12.4 Hz, 1H),
4.48 (d, J=12.4 Hz, 1H), 3.55 (dd, J=10.0, 4.4 Hz, 1H), 3.47 (dd, J=
10.0, 6.4 Hz, 1H), 3.21 (dd, J=14.4, 4.8 Hz, 1H), 3.07 (dd, J=14.4,
7.2 Hz, 1H), 2.02 (s, 3H), 1.96 ppm (s, 3H); 13C NMR: d=169.4, 169.2,
153.0, 136.8, 133.6, 130.3, 129.3, 128.9, 128.4, 128.1, 128.1, 128.0, 127.9,
127.4, 125.1, 77.6, 76.0, 73.6, 70.4, 69.1, 67.3, 37.5, 20.9, 20.5 ppm; HRMS:
calcd for C24H26O8SNa [M+Na]+: 474.1348; found: 497.1256.
Phenyl 4,6-di-O-benzyl-2,3-carbonyl-1-thio-b-d-galactopyranoside (12):
Triphosgene (0.30 g, 1.68 mmol) was added to a solution of phenyl 4,6-di-
O-benzyl-1-thio-b-d-galactopyranoside[28] (1.50 g, 3.31 mmol) and Et3N
(5 mL, 35.97 mmol) in CH2Cl2 (20 mL) at 08C. After the mixture had
been stirred at 08C for 2 h, sat. NaHCO3 and CHCl3 were added. The
aqueous layer was extracted with CHCl3, and the combined layers were
washed with brine. After drying of the mixture over Na2SO4, the solvent
was evaporated. The crude mixture was purified by silica gel column
chromatography (hexane:EtOAc 7:3) to give carbonate 12 (1.50 g, 96%):
[a]2D4 =ꢀ56.6 (c=0.50 in CHCl3); 1H NMR: d=7.50 (d, J=6.8 Hz, 2H),
7.23–7.13 (m, 13H), 4.82 (d, J=9.6 Hz, 1H), 4.70 (d, J=11.2 Hz, 1H),
4.48–4.38 (m, 4H), 4.26 (dd, J=11.2, 2.4 Hz, 1H), 4.18 (s, 1H), 3.76 (t,
J=6.4 Hz, 1H), 3.61–3.59 ppm (m, 2H); 13C NMR: d=152.7, 137.5,
137.0, 133.8, 130.2, 129.0, 128.7, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6,
84.4, 83.3, 78.2, 74.2, 73.6, 71.9, 68.0 ppm; HRMS: calcd for C27H26O6SNa
[M+Na]+: 501.1451; found: 501.1439.
Phenyl 4,6-O-benzylidene-2,3-carbonyl-1-thio-b-d-galactopyranoside (3):
Triphosgene (3.30 g, 11.12 mmol) was added to a solution of phenyl 4,6-
O-benzylidene-1-thio-b-d-galactopyranoside[27] (3.30 g, 9.59 mmol) and
Et3N (10 mL, 71.75 mmol) in CH2Cl2 (30 mL) at 48C. The mixture was
stirred at 48C for 30 min, then sat. NaHCO3 was added. The aqueous
layer was extracted with CHCl3. The combined layers were washed with
brine. After drying of the extracts over Na2SO4, the solvent was removed
in vacuo. The mixture was purified by recrystallisation from EtOAc and
hexane to give carbonate 3 (3.24 g, 88%): m.p. 186–1878C; [a]2D4 =ꢀ83
(c=0.54 in CHCl3); 1H NMR: d=7.68 (d, J=7.2 Hz, 2H), 7.39–7.23 (m,
8H), 5.51 (s, 1H), 4.93 (d, J=9.6 Hz, 1H), 4.59 (s, 1H), 4.49 (t, J=
9.6 Hz, 1H), 4.34 (dd, J=11.2, 2.4 Hz, 1H), 4.09 (m, 1H), 3.65 ppm (s,
1H); 13C NMR: d=152.5, 136.6, 135.4, 129.5, 129.2, 129.1, 128.4, 128.2,
126.3, 10.7, 83.1, 81.2, 77.2, 72.6, 71.7, 70.0, 69.7 ppm; elemental analysis:
calcd (%) for C20H18O6S: C 62.16, H 4.70; found: C 61.99, H 4.75.
6898
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6894 – 6901

Endocyclic Cleavage of Glycopyranosides
FULL PAPER
Reduction and chloride addition of 12: 4.0m HCl dioxane solution was
added to a suspension of 12 (269.3 mg, 0.563 mmol) and NaBH3CN
(750 mg, 11.94 mmol) in THF (10 mL) at 08C in the presence of methyl
orange until the colour of the reaction mixture became deep red. The
mixture was stirred at between 08C and room temperature for 6 h. Re-
Anomerisation of 18: BF3·OEt2 (53 mL, 0.426 mmol) was added to a solu-
tion of b-thioglycoside 18 (121 mg, 0.213 mmol) in CH2Cl2 (2.8 mL) at
ꢀ308C. After the mixture had been stirred for 12 h, sat. NaHCO3 was
added. The aqueous layer was extracted with EtOAc, and the organic
layer was washed with brine. After drying of the extracts over Na2SO4,
the solvent was removed in vacuo. The residue was purified by prepara-
tive TLC (hexane:EtOAc 4:1) to give the b-thioglycoside 18 (96 mg,
1
duced compound 13: [a]2D4 =ꢀ48.8 (c=1.5 in CHCl3); H NMR: d=7.50–
7.19 (m, 15H), 5.01 (dd, J=9.6, 4.8 Hz, 1H), 4.68 (d, J=11.2 Hz, 1H),
4.63 (dd, J=4.8, 2.8 Hz, 1H), 4.51 (d, J=10.8 Hz, 1H), 4.47 (d, J=
12.0 Hz, 1H), 4.46 (d, J=12.0 Hz, 1H), 3.89 (t, J=2.8 Hz, 1H), 3.74 (m,
1H), 3.37 (dd, J=9.2, 6.0 Hz, 1H), 3.49 (dd, J=9.2, 6.0 Hz, 1H), 3.78
(dd, J=9.2, 6.0 Hz, 1H), 3.27–3.25 ppm (m, 2H); 13C NMR: d=153.8,
137.2, 136.7, 134.5, 1303, 129.3, 129.1, 128.6, 128.6, 128.5, 128.5, 128.4,
128.3, 128.0, 127.9, 127.1, 81.3, 77.4, 76.3, 75.8, 73.6, 70.4, 69.9, 37.6 ppm.
Chloride adduct 14 (as a mixture): 13C NMR: d=153.4, 137.1, 136.5,
133.3, 133.1, 131.6, 129.5, 129.3, 129.2, 129.0, 128.6, 128.6, 128.5, 128.4,
128.1, 128.1, 128.0, 127.9, 81.2, 80.0, 78.9, 78.7, 77.2, 76.0, 75.9, 73.6, 73.6,
70.9, 70.4, 70.3, 70.2, 69.4 ppm; HRMS: calcd for C27H27ClO6SNa
[M+Na]+: 537.1109; found: 537.1111.
79%) and a-thioglycoside 19 (11.8 mg, 10%). a-thioglycoside 19: [a]D24
=
250.0 (c=1.0 in CHCl3); 1H NMR: d=7.49–7.47 (m, 2H), 7.32–7.22 (m,
18H), 5.73 (d, J=4.8 Hz, 1H), 4.80 (d, J=11.2 Hz, 1H), 4.66 (d, J=
9.6 Hz, 1H), 4.63 (d, J=9.2 Hz, 1H), 4.59 (d, J=12.0 Hz, 1H), 4.52–4.44
(m, 3H), 4.21 (m, 1H), 4.04 (t, J=9.2 Hz, 1H), 3.83 (dd, J=10.4, 3.6 Hz,
1H), 3.73 ppm (d, J=10.4 Hz, 1H); 13C NMR: d=158.5, 137.6, 137.2,
134.4, 132.8, 132.3, 131.9, 129.1, 129.0, 128.9, 128.9, 128.4, 128.3, 128.3,
128.1, 127.9, 127.8, 127.7, 84.8, 79.4, 77.2, 74.5, 73.5, 73.1, 72.8, 67.8, 59.8,
47.8 ppm; elemental analysis: calcd (%) for C34H33NO5S: C 71.93, H 5.86,
N 2.47; found: C 71.66, H 5.76, N 2.33.
Phenyl
N-benzyl-2-amino-4,6-di-O-acetyl-2,3-N,O-carbonyl-2-deoxy-1-
Anomerisation and intramolecular Friedel–Crafts reaction of 15:
BF3·OEt2 (53 mL, 0.428 mmol) was added to a solution of a-thioglycoside
15 (111.1 mg, 0.214 mmol) in CH2Cl2 (3.0 mL) at room temperature.
After the mixture had been stirred at room temperature for 1 h, sat.
NaHCO3 was added. The aqueous layer was then extracted with EtOAc.
The combined layers were washed with brine and dried over Na2SO4.
After evaporation, the residue was purified by preparative TLC
(CHCl3:EtOAc 20:1) to give the a-thioglycoside 15 (37.5 mg, 34%), b-
thioglycoside 4 (8.7 mg, 8%), and Friedel–Crafts products 16 and 17
(45.2 mg, 41%). Intramolecular Friedel–Crafts compound 16: 1H NMR:
d=7.34–7.12 (m, 8H), 7.23 (dd, J=7.6, 1.5 Hz, 1H), 7.15 (dd, J=8.5, 7.6,
Hz, 2H), 7.11 (dd, J=8.5, 1.5 Hz, 2H), 7.00 (d, J=7.1 Hz, 1H), 5.14 (dd,
J=5.5, 2.5 Hz, 1H), 5.07 (ddd, J=6.1, 4.1, 3.6 Hz, 1H), 4.59 (d, J=
11.6 Hz, 1H), 4.56 (d, J=11.6 Hz, 1H), 4.31 (dd, J=5.5, 3.0 Hz, 1H),
4.23 (d, J=16.7 Hz, 1H), 4.07 (d, J=16.7 Hz, 1H), 3.98 (dd, J=6.1,
2.5 Hz, 1H), 3.91 (dd, J=10.5, 3.6 Hz, 1H), 3.80 (dd, J=10.5, 4.1 Hz,
1H), 2.10 ppm (s, 3H); 13C NMR: d=170.24, 156.42, 137.28, 134.97,
133.37, 131.53, 131.13, 129.88, 128.80, 128.53, 128.53, 128.13, 128.00,
127.93, 126.98, 126.61, 76.88, 73.68, 71.90, 71.76, 68.96, 57.22, 50.65, 42.73,
21.06 ppm; HRMS: calcd for C29H29NO6SNa [M+Na]+: 542.1608; found:
542.1614. Intramolecular Friedel–Crafts compound 17: 1H NMR: d=7.3–
7.1 (m, 14H), 5.43 (dd, J=5.0, 3.0 Hz, 1H), 5.12 (dd, J=8.6, 3.0 Hz, 1H),
4.58 (m, 1H), 4.49 (d, J=12.1 Hz, 1H), 4.18 (s, 1H), 4.08 (m, 1H), 4.04
(dd, J=5.0, 3.0 Hz, 1H), 3.58 (dd, J=10.1, 3.5 Hz, 1H), 3.45 (dd, J=10.1,
5.0 Hz, 1H), 2.00 ppm (s, 3H); 13C NMR (selected data): d=170.34,
133.39, 126.56, 75.94, 73.55, 72.17, 69.94, 68.75, 57.42, 50.56, 42.84,
20.67 ppm.
thio-b-d-glucopyranoside (20): A mixture of phenyl N-benzyl-2-amino-
4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-1-thio-b-d-glucopyranoside
(1.0 g, 2.11 mmol) in AcOH (8 mL) and H2O (2 mL) was heated at
1008C for 3 h. After the mixture had been cooled to room temperature,
the solvent was evaporated, and the residue was washed with Et2O. The
residue was dissolved in pyridine (10 mL) and Ac2O (10 mL) and stirred
overnight. After evaporation of the solvent, the residue was purified by
silica gel column chromatography (CHCl3: EtOAc 4:1!1:1) to give the
diacetate 20 (920 mg, 93%): [a]2D4 =ꢀ86.4 (c=0.5 in CHCl3); 1H NMR:
d=7.39–7.26 (m, 10H), 5.23 (t, J=9.2 Hz, 1H), 4.77–4.74 (m 3H), 4.20–
4.18 (m, 2H), 4,14 (t, J=11.2 Hz, 1H), 3.71 (m, 1H), 3.51 (t, J=9.6 Hz,
1H), 2.09 (s, 3H), 2.04 ppm (s, 3H); 13C NMR: d=170.2, 169.0, 158.3,
135.7, 132.8, 131.5, 129.0, 128.6, 128.1, 127.6, 86.6, 79.8, 77.2, 67.4, 62.3,
60.2, 47.6, 20.9, 20.8 ppm; elemental analysis: calcd (%) for C24H25NO7S:
C 61.13, H 5.34, N 2.97; found: C 61.00, H 5.29, N 2.90.
Anomerisation of 20: BF3·OEt2 (22 mL, 0.175 mmol) was added to a solu-
tion of b-thioglycoside 20 (41.2 mg, 0.0875 mmol) in CH2Cl2 (1.1 mL) at
ꢀ308C. After the mixture had been stirred for 12 h, sat. NaHCO3 was
added. The aqueous layer was extracted with EtOAc, and the organic
layer was washed with brine. After drying of the extracts over Na2SO4,
the solvent was removed in vacuo. The residue was purified by prepara-
tive TLC to give the b-thioglycoside 20 (19.4 mg, 47%) and a-thioglyco-
side 21 (11.1 mg, 27%). a-thioglycoside 21: [a]2D4 =218.9 (c=0.58 in
CHCl3); 1H NMR: d=7.40–7.26 (m, 10H), 5.38 (d, J=4.8 Hz, 1H), 5.29
(t, J=10.0 Hz, 1H), 4.79 (d, J=14.4 Hz, 1H), 4.78 (t, J=13.2 Hz, 1H),
4.33–4.26 (m, 2H), 4.17 (d, J=14.4 Hz, 1H), 4.08 (d, J=12.0 Hz, 1H),
3.59 ppm (dd, J=12.0 Hz, 4.4 Hz, 1H); 13C NMR: d=170.3, 169.1, 157.8,
134.0, 132.1, 132.0, 129.2, 129.0, 128.9, 128.5, 128.2, 84.8, 75.8, 70.5, 68.1,
61.7, 59.8, 48.0, 48.0, 20.7 ppm; elemental analysis: calcd (%) for
C24H25NO7S: C 61.13, H 5.34, N 2.97; found: C 60.97, H 5.19, N 2.88.
Phenyl
N-benzyl-2-amino-4,6-di-O-benzyl-2,3-N,O-carbonyl-2-deoxy-1-
thio-b-d-glucopyranoside (18): A mixture of phenyl N-benzyl-2-amino-
4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-1-thio-b-d-glucopyranos-
ACHTUNGTRENNUNG
ide[13b] (1.0 g, 2.11 mmol) in AcOH (8 mL) and H2O (2 mL) was heated
Phenyl
4-O-acetyl-6-O-benzyl-2,3-carbonyl-1-thio-b-d-glucopyranoside
at 1008C for 3 h. After the mixture had been cooled to room tempera-
ture, the solvent was evaporated, and the residue was washed with Et2O.
The residue was dissolved in dimethylformamide (DMF; 3 mL) and
benzyl bromide (0.75 mL, 6.33 mmol), then NaH (253 mg, 6.33 mmol)
was added at 08C. After the mixture had been stirred at room tempera-
ture overnight, Et3N was added to destroy the excess benzyl bromide.
After addition of sat. NaHCO3, the aqueous layer was extracted several
times with EtOAc. The combined layers were washed with brine. After
drying of the extract over Na2SO4, the solvent was evaporated. The resi-
due was purified by silica gel column chromatography (hexane:EtOAc
7:3) to give the dibenzylated compound 18 (1.05 g, 88%): [a]2D4 =ꢀ27.2
(c=0.74 in CHCl3); 1H NMR: d=7.40–7.17 (m, 20H), 4.87 (d, J=
11.2 Hz, 1H), 4.76–4.73 (m, 3H), 4.55 (d, J=11.6 Hz, 1H), 4.53 (d, J=
11.2 Hz, 1H), 4.48 (d, J=11.6 Hz, 1H), 4.17 (t, J=11.2 Hz, 1H), 3.87 (t,
J=8.8 Hz, 1H), 3.74 (dd, J=10.4, 1.4 Hz, 1H), 3.69 (dd, J=10.4, 4.8 Hz,
1H), 3.58 (m, 1H), 3.45 ppm (t, J=11.2 Hz, 1H); 13C NMR: d=159.0,
137.9, 137.1, 136.1, 132.3, 132.2, 128.9, 128.5, 128.3, 128.2, 128.1, 128.1,
127.9, 127.8, 127.6, 127.5, 127.5, 86.4, 83.4, 79.9, 77.2, 73.8, 73.4, 73.2, 68.6,
60.4, 47.6 ppm; elemental analysis: calcd (%) for C34H33NO5S: C 71.93, H
5.86, N 2.47; found: C 71.69, H 5.58, N 2.34.
(22): HCl (4.0m HCl dioxane solution) was added to a suspension of
compound 1 (1.50 g, 3.89 mmol) and NaBH3CN (4.50 g, 71.61 mmol) in
THF (40 mL) at 48C in the presence of methyl orange until the solution
became red. The mixture was stirred at 48C under nitrogen atmosphere
for 2 h. Brine was then added. After 30 min, the mixture was diluted with
brine and EtOAc. The aqueous layer was extracted with EtOAc. The
combined layers were washed with brine. After drying of the mixture
over Na2SO4, the solvent was evaporated. The residue was purified by
silica gel column chromatography (hexane:EtOAc 7:3!1:1) to give the
4-OH product. The 4-OH product was dissolved in pyridine (10 mL), and
Ac2O (10 mL) was added at room temperature. After 2 h, the mixture
was evaporated and the residue was purified by silica gel column chroma-
tography (hexane:EtOAc 7:3) to give product 22 (1.50 g, 90%) as a col-
ourless oil: [a]2D4 =ꢀ7.7 (c=1.0 in CHCl3); 1H NMR: d=7.57 (d, J=
7.2 Hz, 2H), 7.28–7.19 (m, 8H), 5.19 (t, J=9.2 Hz, 1H), 4.82 (d, J=
9.6 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.45 (d, J=12.0 Hz, 1H), 4.26 (t,
J=10.4H, 1H), 3.83 (t, J=9.6 Hz, 1H), 3.61 (m, 1H), 3.58–3.54 (m, 2H),
1.94 ppm (s, 3H); 13C NMR: d=168.7, 152.1, 137.4, 134.6, 129.2, 129.0,
128.6, 128.3, 127.7, 127.7, 82.6, 82.2, 78.9, 75.9, 73.6, 68.2, 67.7, 20.7 ppm;
Chem. Eur. J. 2009, 15, 6894 – 6901
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6899

S. Manabe, Y. Ito et al.
elemental analysis: calcd for C22H22O7S: C 61.38, H 5.15; found: C 61.38,
H 5.24.
After evaporation of the solvent, the crude residue was purified by silica
gel column chromatography (hexane:EtOAc 7:3) to give the acetate 31
(0.54 g, 96%): [a]2D4 =ꢀ9.4 (c=0.90 in CHCl3); 1H NMR: d=7.27–7.20
(m, 5H), 5.27 (t, J=10.0 Hz, 1H), 4.71 (d, J=7.6 Hz, 1H), 4.53 (d, J=
12.0 Hz, 1H), 4.45 (d, J=12.0 Hz, 1H), 4.34 (t, J=11.6 Hz, 1H), 4.10 (m,
1H), 3.68 (m, 1H), 3.57–3.48 (m, 2H), 3.51 (s, 3H), 1.95 ppm (s, 3H);
13C NMR: d=169.26, 153.01, 137.68, 128.69, 128.18, 128.15, 100.68, 80.34,
78.06, 77.64, 73.95, 68.57, 57.10, 20.95 ppm.
Friedel–Crafts reaction of 22: BF3·OEt2 (43 mL, 0.347 mmol) was added
to a solution of b-thioglycoside 22 (74.6 mg, 0.173 mmol) in toluene
(2.2 mL) at ꢀ308C. The mixture was stirred at room temperature. Sat.
NaHCO3 was then added. The aqueous layer was extracted with EtOAc.
The combined layers were washed with brine and dried over Na2SO4.
After evaporation of the solvent, the crude residue was purified by prep-
arative TLC (hexane:EOAc 7:3) to give the recovered b-thioglycoside 22
(32.1 mg, 43%) and Friedel–Crafts product 24 (41.0 mg, 45%). Toluene
Friedel–Crafts adduct 24: 1H NMR: d=7.39–7.28 (m, 10H), 7.18 (d, J=
8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 5.05 (dd, J=4.0, 1.5 Hz, 1H), 4.95
(dd, J=9.0, 1.5 Hz, 1H), 4.67 (dd, J=5.5, 4.0 Hz, 1H), 4.54 (d, J=
11.6 Hz, 1H), 4.46 (d, J=11.6 Hz, 1H), 3.91 (m, 1H), 3.50 (d, J=10.0,
3.6 Hz, 1H), 3.37 (d, J=10.0, 4.6 Hz, 1H), 2.32 (s, 3H), 2.48 (brs, 1H),
1.99 ppm (s, 3H); 13C NMR: d=169.68, 153,50, 138.36, 137.03, 133.18,
132.40, 131.81, 129.55, 129.12, 128.48, 128.39, 128.19, 127.93, 127.84, 79.35,
76.51, 73.57, 72.03, 69.54, 68.00, 55.49, 21.29, 20.69 ppm; HRMS: calcd for
C29H30O7SNa [M+Na]+: 545.1604; found: 545.1623.
Methyl 4-O-acetyl-6-O-benzyl-2,3-carbonyl-a-d-glucopyranoside (32):
BF3·OEt2 (49 mL, 0.400 mmol) was added to a solution of b-thioglycoside
31 (70.5 mg, 0.200 mmol) in toluene (2.6 mL) at ꢀ308C. After 12 h, the
mixture was diluted with sat. NaHCO3 and EtOAc. The aqueous layer
was extracted with EtOAc. The combined layers were washed with brine
and dried over Na2SO4. After filtration, the solvent was removed in
vacuo. The residue was purified by preparative TLC (hexane:EtOAc 7:3)
to give a isomer 32 (62.3 mg, 88%): [a]2D4 =125.8 (c=0.73 in CHCl3);
1H NMR: d=7.27–7.19 (m, 5H), 5.35 (t, J=9.6 Hz, 1H), 5.10 (d, J=
3.2 Hz, 1H), 4.70 (t, J=11.6 Hz, 1H), 4.53 (d, J=12.0 Hz, 1H), 4.42 (dd,
J=12.0, 3.2 Hz, 1H), 3.74 (m, 1H), 3.54–3.46 (m, 2H), 3.46 (s, 2H),
1.92 ppm (s, 3H); 13C NMR: d=168.74, 152.71, 137.27, 128.32, 127.82,
127.78, 95.63, 77.05, 76.84, 73.54, 71.14, 68.42, 67.23, 56.10, 20.57 ppm.
Friedel–Crafts reaction of 25: BF3·OEt2 (42 mL, 0.347 mmol) was added
to a solution of b-thioglycoside 25 (82.2 mg, 0.172 mmol) in toluene
(2.2 mL) at ꢀ308C. The mixture was stirred at room temperature. Sat.
NaHCO3 was then added. The aqueous layer was extracted with EtOAc.
The combined layers were washed with brine and dried over Na2SO4.
After evaporation of the solvent, the crude residue was purified by prep-
arative TLC (hexane:EOAc 7:3) to give the recovered b-thioglycoside 25
(49.4 mg, 60%) and Friedel–Crafts product 27 (10.0 mg, 15%). Toluene
Friedel–Crafts adduct 27 (only S isomer data given): 1H NMR: d=7.36–
7.04 (m, 19H), 4.82 (dd, J=4.0, 1.5 Hz, 1H), 4.56–4.47 (m, 4H), 4.32 (m,
1H), 3.83 (m, 1H), 3.61 (t, J=9.2 Hz, 1H), 3.62 (m, 2H), 3.30 (m, 2H),
2.17 ppm (s, 3H); 13C NMR: d=153.8, 138.2, 137.2, 136.7, 133.5, 132.9,
132.7, 132.3, 132.1, 129.4, 129.3, 129.0, 128.8, 128.7, 127.7, 79.3, 78.8, 78.2,
78.1, 77.9, 77.2, 74.5, 74.2, 73.6, 73.5, 70.1, 69.8, 55.0, 21.3 ppm.
Phenyl 4,6-O-benzylidene-2,3-carbonyl-1-thio-b-d-mannopyranoside: Tri-
phosgene (0.81 g, 2.73 mmol) was added in several portions to a solution
of phenyl 4,6-O-benzylidene-1-thio-b-d-mannopyranoside[29] (1.18 g,
3.28 mmol) and Et3N (5 mL, 3.59 mmol) in CH2Cl2 (10 mL) at 48C. After
30 min, the mixture was diluted with CH2Cl2, and sat. NaHCO3 was
added. The aqueous layer was extracted with CH2Cl2. After drying of the
organic layers over Na2SO4, the solvent was evaporated. The residue was
purified by silica gel column chromatography (CHCl3) to give the carbon-
ate (1.00 g. 79%): m.p. 149–1508C; [a]2D4 =ꢀ123 (c=0.98 in CHCl3);
1H NMR: d=7.47–7.18 (m, 10H), 5.52 (s, 1H), 4.98 (d, J=2.4 Hz, 1H),
4.93 (dd, J=6.4, 2.4 Hz, 1H), 4.73 (t, J=6.4 Hz, 1H), 4.34 (dd, J=10.8,
5.2 Hz, 1H), 3.88 (t, J=10.0 Hz, 1H), 3.80 (t, J=10.0 Hz, 1H), 3.36 ppm
(m, 1H); 13C NMR: d=152.68, 136.12, 132.76, 131.98, 129.28, 129.18,
128.44, 128.23, 125.92, 101.86, 84.93, 78.49, 77.1, 76.32, 68.37, 68.34 ppm;
HRMS: calcd for C20H18O6SNa [M+Na]+: 409.0722; found: 409.0739.
Anomerisation and reduction of 28: BF3·OEt2 (0.16 mL, 1.23 mmol) was
added to a solution of benzylidene acetal 28 (200 mg, 0.649 mmol) and
Et3SiH (1.2 mL, 7.78 mmol) in CH2Cl2 (8.6 mL) at 08C. After 12 h, sat.
NaHCO3 was added. The aqueous layer was extracted with CHCl3. The
combined layers were washed with sat. NaHCO3 and brine. After drying
of the organic layers over Na2SO4, the solvent was removed in vacuo.
The crude residue was purified by preparative TLC (hexane:EtOAc 3:7)
to give a product 29 (88.2 mg, 44%) and reduced diol 30 (41.5 mg, 21%).
a product 29: [a]2D4 =69.3 (c 0.92 CHCl3); 1H NMR: d=7.29–7.25 (m,
5H), 5.04 (d, J=2.8 Hz, 1H), 4.66 (t, J=10.0 Hz, 1H), 4.55 (d, J=
12.0 Hz, 1H), 4.48 (d, J=12.0 Hz, 1H), 4.09–4.06 (m, 2H), 3.72 (m, 1H),
3.63 (m, 2H), 3.47 (s, 3H), 3.05 ppm (brs, 1H); 13C NMR: d=153.37,
137.15, 128.44, 127.68, 95.73, 79.24, 73.89, 72.31, 70.32, 68.95, 56.02 ppm.
Diol 30: [a]2D4 =ꢀ52.2 (c=1.97 in CHCl3); 1H NMR: d=7.35–7.29 (m,
5H), 4.83 (m, 2H), 4.76 (m, 2H), 4.55 (s, 4H), 3.85 (m, 2H), 3.70–3.54
(m, 2H), 3.39 (s, 3H), 2.91 (d, J=3.2 Hz, 1H), 2.62 ppm (d, J=3.2 Hz
1H); 13C NMR: d=154.42, 137.07, 128.47, 127.80, 77.86, 77.20, 73.72,
72.50, 71.37, 69.76, 59.65 ppm.
Phenyl 4-O-acetyl-6-O-benzyl-2,3-carbonyl-1-thio-b-d-mannopyranoside
(33): HCl (4.0m HCl dioxane solution) was added to a suspension of
phenyl
4,6-O-benzylidene-2,3-carbonyl-1-thio-b-d-mannopyranoside
(1.50 g, 3.89 mmol) and NaBH3CN (4.5 g. 71.61 mmol) in THF (50 mL)
at 48C in the presence of methyl orange until the solution became red.
The mixture was stirred at 48C under a nitrogen atmosphere for 2 h.
Brine was then added. After 30 min, the mixture was diluted with brine
and EtOAc. The aqueous layer was extracted with EtOAc. The combined
layers were washed with brine. After drying of the organic extracts over
Na2SO4, the solvent was evaporated. The residue was purified by silica
gel column chromatography (toluene/EtOAc 9:1!7:3) to give the 4-OH
product. The 4-OH product was dissolved in pyridine (10 mL), and Ac2O
(10 mL) was added at room temperature. After 2 h, the mixture was
evaporated and the residue was purified by silica gel column chromatog-
raphy (toluene/EOAc 4:1) to give product 33 (1.30 g, 78%) as a colour-
less oil: [a]2D4 =ꢀ63 (c=2.2 in CHCl3); 1H NMR: d=7.54–7.52 (m, 2H),
7.35–7.26 (m, 8H), 5.16 (t, J=4.4 Hz, 1H), 5.02–4.98 (m, 2H), 4.85 (dd,
J=7.2, 4.4 Hz, 1H), 4.56 (s, 2H), 3.88 (dd, J=11.2, 5.2 Hz, 1H), 3.73 (dd,
J=10.4, 6.4 Hz, 1H), 3.66 (dd, J=10.4, 5.2 Hz, 1H), 2.06 ppm (s, 3H);
13C NMR: d=169.0, 152.6, 137.5, 133.4, 131.4, 131.3, 129.1, 128.5, 128.3,
128.0, 127.8, 127.7, 127.7, 127.6, 124.9, 83.5, 83.3, 78.6, 75.4, 75.4, 73.8,
73.7, 70.1, 66.7, 20.8 ppm; HRMS: calcd for C22H22O7SNa [M+Na]+:
453.0984; found: 453.0972.
Methyl
4-acetyl-6-O-benzyl-2,3-carbonyl-b-d-glucopyranoside
(31):
BF3·OEt2 (0.75 mL, 7.10 mmol) was added to a solution of methyl 4,6-O-
benzylidene-2,3-carbonyl-b-d-glucopyranoside (1.00 g, 3.25 mmol) and
Et3SiH (6.1 mL, 38.19 mmol) in CH2Cl2 (20 mL) at ꢀ308C. After 2 h, sat.
NaHCO3 was added. The aqueous layer was extracted with CHCl3. The
combined layers were washed with brine. After drying of the mixture,
the solvent was removed. The residue was purified by silica gel column
chromatography (hexane:EtOAc 1:1) to give methyl 6-O-benzyl-2,3-car-
bonyl-b-d-glucopyranoside: (0.87 g, 87%): [a]2D4 =ꢀ41.5 (c=1.19 in
CHCl3); 1H NMR: d=7.35–7.24 (m, 5H), 4.70 (d, J=7.6 Hz, 1H), 4.61
(d, J=12.0 Hz, 1H), 4.55 (d, J=12.0 Hz, 1H), 4.20 (t, J=10.0 Hz, 1H),
4.11 (m, 1H), 3.96 (dd, J=11.6, 7.6 Hz, 1H), 3.81 (m, 1H), 3.73 (dd, J=
10.0, J=5.2 Hz, 1H), 3.53 ppm (s, 3H); 13C NMR: d=153.15, 136.89,
128.50, 128.07, 127.87, 127.70, 100.41, 95.75, 82.38, 77.72, 77.20, 76.04,
73.91, 73.85, 70.15, 69.73, 56.87 ppm.
Anomerisation experiment with 33: BF3·OEt2 (52 mL, 0.418 mmol) was
added to a solution of b-thioglycoside 33 (90 mg, 0.209 mmol) in CH2Cl2
(2.7 mL) at 48C. After the mixture had been stirred at 48C for 3 h, sat.
NaHCO3 was added. The aqueous layer was extracted with CHCl3. The
combined layers were washed with brine. After drying of the mixture
over Na2SO4, the solvent was removed in vacuo. The residue was purified
by preparative TLC (hexane/EtOAc 7:3) to recover the starting material
33 (90 mg, quant.).
A solution of the alcohol prepared above (0.50 g, 16.13 mmol) and Ac2O
(10 mL) in pyridine (10 mL) was stirred at room temperature for 3 h.
6900
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6894 – 6901

Endocyclic Cleavage of Glycopyranosides
FULL PAPER
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Acknowledgements
We thank Dr. Hiroko Satoh for helpful discussions. S.M. was supported
by a Grant-in-Aid for Scientific Research (C) (grant nos. 19590032 and
21590036) from the Japan Society for Promotion of Science and by an In-
centive Research Grant from RIKEN. We thank Dr. Teiji Chihara and
Ms. Keiko Yamada for elemental analyses and Dr. Kaori Otsuki and Dr.
Masaya Usui at the Research Resource Center of RIKENꢂs Brain Sci-
ence Center and Dr. Yayoi Hongo of the Advanced Technology Support
Division, RIKEN Advanced Science Institute, for high-resolution MS
measurements. We also thank Ms. Akemi Takahashi for her technical as-
sistance.
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Received: January 10, 2009
Published online: June 16, 2009
Chem. Eur. J. 2009, 15, 6894 – 6901
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6901