Two straightforward strategies for the synthesis of thiodisaccharides with a furanose unit as the nonreducing end

Article abstract of DOI:10.1002/ejoc.200700874

Thiodisaccharides having a 1-thiopentofuranose nonreducing end were synthesized by two routes starting from per-O-acylaldofuranoses with arabino, ribo, and xylo configurations. These glycosyl donors were converted into S-glycosyl isothiourea derivatives a

Full text of DOI:10.1002/ejoc.200700874

FULL PAPER
DOI: 10.1002/ejoc.200700874
Two Straightforward Strategies for the Synthesis of Thiodisaccharides with a
Furanose Unit as the Nonreducing End
Evangelina Repetto,[a] Carla Marino,[a] M. Laura Uhrig,[a] and Oscar Varela*[a]
Keywords: Thiodisaccharides / Furanose / Glycosylation / Catalysis / Molybdenum / Michael addition
Thiodisaccharides having a 1-thiopentofuranose nonreduc- Alternatively, the MoO2Cl2-promoted glycosylation of the
ing end were synthesized by two routes starting from per-O-
acylaldofuranoses with arabino, ribo, and xylo configura-
tions. These glycosyl donors were converted into S-glycosyl
isothiourea derivatives as precursors of 1-thiofuranose units,
which were generated in situ and trapped by a sugar enone
to produce, by Michael addition, the thioglycosidic linkage.
thiol group of 6-thiosugar derivatives by per-O-acylfuranose
led to thiodisaccharides with exclusive 1,2-trans diastereo-
control.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
in nucleic acids and arabinofuranose is found in soil bacte-
ria, fungi, and plants.[9] Arabinose and galactose in the fu-
ranose form are constituents of polysaccharides of myco-
bacteria. Inhibition of the enzymes that assemble these po-
lyfuranosides prevents proliferation of pathogenic myco-
bacteria.[10] Recently, thioimidoyl α--arabinofuranosides
have been described as the first potent inhibitors of an
arabinofuranosidase.[11] In view of the previous considera-
tions and in connection with our studies on the synthesis
and inhibitory activity of S-linked saccharides,[12–14] we ex-
plored the construction of thiodisaccharides containing a
pentofuranose unit as potential inhibitors of pentofuranos-
idases. We report here two successful approaches for the
synthesis of such thiodisaccharides starting from readily
available per-O-acylated pentofuranoses.
Introduction
The search for new glycosidase inhibitors and stable
sugar mimetics has led to oligosaccharide analogues with
the glycosidic oxygen atom substituted by sulfur or other
heteroatoms. The S-glycosides are carbohydrate mimetics
that are usually resistant to metabolic processes.[1,2] The in-
terglycosidic sulfur atom in S-glycosides may act as a hy-
drogen-bond acceptor, which, as in the natural substrate,
could play an important role in ligand binding and espe-
cially in the case of enzyme inhibitors and enzyme-resistant
scaffolds.[3] Therefore, thiooligosaccharides have attracted
considerable attention, and a number of approaches to their
synthesis have been reported.[2,4,5] However, this large body
of information refers mainly to thiooligosaccharides consti-
tuted by pyranose units, whereas just a very few examples
were found of thiodisaccharides having a furanose moiety
as a constituent. For instance, 1,2:5,6-di-O-isopropylidene-
3-O-trifluoromethylsulfonyl-α--gulofuranose was con-
verted into the S-α-sialyl(2Ǟ3)-3-thiogalactofuranose de-
rivative, which on deprotection led to the galactopyranose
isomer as the major product.[6] The synthesis of a glyconu-
cleoside containing a ribofuranosyl residue linked to the
thiol group of 3Ј-thiothymine, has recently been reported.[7]
Heteroatom analogues of oligosaccharides of galactofur-
anose having the ring oxygen atom replaced by sulfur have
been prepared.[8]
Results and Discussion
The Michael addition of thiosugars to carbohydrate-de-
rived enones constitutes a direct procedure for the construc-
tion of an S-linkage to the β carbon of the α,β-unsaturated
carbonyl group of the enone.[12,14] Witczak[15] and Thiem[16]
employed this methodology for the synthesis of a number of
thiodisaccharides starting from levoglucosenone, or other
enones, and 1-thiopyranoses as S-glycosyl donors. To apply
this procedure, we tried unsuccessfully to prepare tri-O-ben-
zoyl-1-thio--arabinofuranose by the methods described
for pyranoses,[17] as the disulfide was mainly produced. The
tendency of thiofuranoses to undergo self-condensation
and other side reactions has been reported.[6] However, we
have described that 1-thiosugars generated in situ from S-
glycosyl isothiourea derivatives can be trapped by a sugar
enone to yield the corresponding thiodisaccharide.[12] Gly-
cosyl isothiourea derivatives may be readily prepared start-
The interest in furanose sugars arises from the fact that
they are widely distributed in nature. Ribofuranose occurs
[a] CIHIDECAR-CONICET, Departamento de Química Orgá-
nica, Facultad de Ciencias Exactas y Naturales, Universidad de
Buenos Aires, Pabellón II, Ciudad Universitaria,
1428 Buenos Aires, Argentina
Fax: +4576-3346
E-mail: varela@qo.fcen.uba.ar
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
540
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 540–547

Thiodisaccharides with a Furanose Unit as the Nonreducing End
ing from 1,2-trans-glycopyranosyl acetates.[18] As 1,2,3,5- The configuration of the new stereocenter at C-4, which
tetra-O-benzoyl-α--arabinofuranose (1a) is easily obtained was generated during the conjugate addition, was estab-
1
by direct benzoylation of -arabinose at high tempera- lished as R on the basis of the H NMR spectrum of 4. As
ture,[19] we studied the glycosylation of this compound with 4-H is coupled with the adjacent methylene protons, the
thiourea by using BF3·OEt2 as a catalyst. Thus, a solution small coupling constant values (J3ax,4 = 4.7 Hz, J3eq,4
=
of 1a and thiourea in acetonitrile was heated under reflux 1.8 Hz) indicate that 4-H is equatorially oriented. Further-
in the presence of BF3·OEt2 to afford α-S-glycosyl isothiou- more, the small value for the coupling between 1Ј-H and
rea 2 (Scheme 1). In the NMR spectra of 2, the C-1 signal 2Ј-H (J1Ј,2Ј Ͻ1 Hz) is indicative of an 1Ј,2Ј-trans stereo-
showed a strong upfield shift (relative to that of 1a) as ob- chemistry[11,13] (α anomeric configuration) for the furanose.
served for thioglycosylation of per-O-acylated fu-
Michael addition to sugar enone 3 was studied for other
ranoses[11,13] and the J1,2 value (Ͻ1 Hz) indicated the α con- per-O-acylated furanoses. Thus, commercially available 1-
figuration for the anomeric center (1,2-trans thioglyco- O-acetyl-2,3,5-tri-O-benzoyl-β--ribofuranose (5) was
side).[19,20] As benzoylation of arabinose also provides β an- treated with thiourea in the presence of BF3·OEt2 to give
omer 1b, the reaction of this compound with thiourea was S-glycosyl isothiourea 6. The 1H NMR spectrum of 6
conducted under the conditions employed for isomer 1a; S- showed a J1,2 value (3.7 Hz) that suggested the β configura-
glycosyl isothiourea 2 was obtained in good yield. From tion for the anomeric center. However, the Et3N-promoted
these results we can conclude that the Ibatullin reaction can reaction of 6 with 3 led to two products, which were isolated
1
be applied to benzoylated furanoses, even when they pos- by column chromatography. The H NMR spectra of both
sess the 1,2-cis configuration. Therefore, the mixture of an- 7 and 8 exhibited small values for J3ax,4 and J3eq,4, which is
omers 1a, 1b may be employed for the synthesis of 2.
indicative of, as in the case of 4, the α--threo configuration
Compound 2, without isolation, was treated with trieth- of the hexopyranosid-2-ulose moiety. The substantial differ-
ylamine (Et3N) to promote the formation of the 1-thioal- ences observed for the signals of the anomeric protons of
dose derivative as the thioglycosyl donor.[18] Addition of 2- the 1-thiofuranose unit of 7 and 8 suggested that anomeri-
propyl
6-O-acetyl-2,3-dideoxy-α--glycero-hex-3-enopyr- zation took place during the reaction. The anomeric configu-
anosid-2-ulose (3) to the reaction mixture led to the forma- ration of ribofuranosides was tentatively assigned on the
tion of thioulose 4. The Michael addition of the nucleo- basis of the relative chemical shifts and coupling constants
philic 1-thioaldose, released from 2, to enone 3 was highly of the anomeric proton.[21] Thus, 7 showed the 1-H reso-
diastereoselective and took place from the face of the py- nance (J1Ј,2Ј = 3.7 Hz) at higher field than that of 8 (J1Ј,2Ј
ranone opposite the axially oriented anomeric substituent. = 6.0 Hz) and was assigned as the β anomer. These assign-
Scheme 1. Reaction conditions: (a) (NH2)2CS, BF3·OEt2, CH3CN, reflux.
Eur. J. Org. Chem. 2008, 540–547
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541

E. Repetto, C. Marino, M. L. Uhrig, O. Varela
FULL PAPER
ments were confirmed by NOE experiments performed on NMR spectrum of 15 was fully assigned by using 2D NMR
thiodisaccharides 17 and 19, which are the respective prod- techniques, and the previous structure assignments were
ucts of carbonyl reduction from 7 and 8, as discussed below. confirmed.
β-S-Glycosyl isothiourea 10 was prepared from commer-
The starting material for the carbonyl reduction–depro-
cial per-O-benzoyl--xylofuranose (9). The corresponding tection sequence was 4-S-(β--ribofuranosyl)-4-thiohex-2-
1-thiosugar derivative, released from 10 with Et3N, was cou- ulose (7; Scheme 3). The reduction of the carbonyl group
pled to enone 3 to give (similar to the ribofuranose series) led to a mixture of diastereoisomers 16 and 17, which were
the anomeric mixture of thiodisaccharides 11 and 12. The isolated by column chromatography. Isomer 17 possessed
ratio 11/12 was about 1.4:1 according to the 1H NMR spec- the 4-thio-α--xylo configuration of the hexopyranose, and
trum, and this mixture could not be separated by column it was the major product. Hydrolysis of the acetyl and ben-
chromatography.
zoyl groups of 17 afforded free thiodisaccharide 18. As for
It is worthy to mention that the thiodisaccharides ob- the analogues in the arabino series (13–15), the structures
tained by the methodology described above were difficult of 16–18 were established on the basis of the NMR spectro-
to isolate in pure form, as they were accompanied by enone scopic data. In particular, the anomeric configuration was
3. During column chromatography, the silica gel seems to determined by ROESY experiments. A characteristic NOE
catalyze the retro-Michael reaction. In fact, the proportion contact[22] between 1Ј-H and 4Ј-H in 17 (not observed for
of 3 increased when 4 was maintained in contact with the 19) indicated that these two protons are on the same face
silica gel for longer periods.
of the furanose ring (β configuration). Similarly, the NOE
The carbonyl functionality of the 4-S-Araf-4-thio-α-- connection between 1Ј-H and 3Ј-H in 19 (not detected for
threo-hexopyranosid-2-ulose derivative (4) was reduced 17) established the α configuration for 19. These results
with sodium borohydride to afford epimeric thiodisacchar- confirmed the previous assignments for the anomeric con-
ides 13 and 14 (Scheme 2). The major diastereoisomer had figuration of 7 and 8, which are the respective precursors
the α--xylo configuration (14) for the hexopyranose moi- of 17 and 19.
ety, as deduced from the NMR spectra. The proton bonded
to the new stereocenter (2-H) showed small coupling con- diastereoselective and led to the 4-S-glycofuranosyl-4-thio-
stant values with 1-H (J1,2 = 3.8 Hz) and 3-Heq (J2,3eq α--xylo-hexopyranosides (14, 17, and 19, respectively) as
The reduction of the carbonyl group of 4, 7, and 8 was
=
3.9 Hz) as expected for a gauche relationship of 2-H with the main products. The ratio for the xylo/lyxo isomers was
these adjacent protons. Furthermore, the large coupling ca. 4:1 (from 4 and 7) and ca. 7:1 (from 8). The selectivity
value between 2-H and 3-Hax (J2,3ax = 12.8 Hz) confirmed observed suggests that the approach of the hydride to the
that the HO group at C-2 is equatorially disposed. In con- C-2 carbonyl is controlled by the axial isopropyl group at
1
trast, in the H NMR of epimer 13, the coupling of 2-H the adjacent stereocenter (C-1). The diastereoselectivity in
with 1-H, 3-Ha and 3-Hb were all small (J1,2 Ͻ1 Hz, J2,3a the reduction of 8 was somewhat higher than that deter-
= 3.0 Hz, J2,3b = 3.9 Hz) in agreement with an axial orienta- mined for 4 and 7. Thioulose 8 bears, in contrast to 4 and
tion for HO-2 (α--lyxo configuration).
7, the 1,2-cis stereochemistry of the thiofuranose ring.
Removal of the ester protecting groups of 14 was ac- Hence, the stereochemical course of the reduction seems to
complished with MeOH/Et3N/H2O (3:1:3) to give the free be influenced by the anomeric configuration of the thiofur-
isopropyl glycoside of thiodisaccharide 15. This product anose. Conformational studies of the thiodisaccharides are
was deionized by elution through a column filled with in progress. The reduction of glycosylthioulosides with
mixed-bed ion-exchange resin, followed by filtration bulkier agents is also under study with the aim to increase
through a reverse phase minicolumn. The first-order 1H the selectivity.
Scheme 2.
542
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Eur. J. Org. Chem. 2008, 540–547

Thiodisaccharides with a Furanose Unit as the Nonreducing End
Scheme 3.
Moreover, we studied an alternative route for the con-
struction of the S-linkage of thiodisaccharides having a fu-
ranose unit as the nonreducing end. For this purpose, read-
ily available per-O-acyl furanoses were selected as glycosyl-
ating agents of the thiol group of a thiosugar. Thus, the
glycosylation of the 6-thiol functionality of 20[23] by per-O-
acyl-β--ribofuranose derivative 5 was conducted as a
model reaction (Scheme 4). The glycosylation was unsuc-
cessful when a Lewis acid (SnCl4) was employed as the cata-
lyst. However, MoO2Cl2 efficiently promoted the formation
of an S-linkage between 5 and 20. This catalyst has recently
been reported[24] for the thioglycosylation of per-O-acety-
lated pyranoses. Similar to pyranoses, the thioglycosylation
of 5 took place under exclusive diastereocontrol to give the
1,2-trans-thioglycoside. The reaction was also applied to
thiosugar 22[25] to afford diastereoselectively the β(1Ǟ6)-S-
linked disaccharide 23.
Conclusions
We have achieved the first two successful routes for the
synthesis of thiodisaccharides having a 1-thiopentofuranose
as the nonreducing end. One of the strategies employed is
based on the Michael addition of a 1-thiofuranose to a
sugar enone. The intermediate 1-thiofuranose was produced
in situ by treatment of S-glycosyl isothiourea derivatives
with a base. The conjugate addition to the enone was dia-
stereoselective, but anomerization occurred for ribo- and
xylofuranoses. Alternatively, per-O-acylfuranoses were em-
ployed for glycosylation of the thiol group of 6-thiosugar
derivatives. This reaction was successfully promoted by neu-
tral MoO2Cl2 to give exclusive 1,2-trans diastereocontrol.
Experimental Section
General Information: Melting points were determined with a
Fisher-Johns apparatus and are uncorrected. Analytical thin-layer
chromatography (TLC) was performed on Silica Gel 60 F254
(Merck) aluminum-supported plates (layer thickness 0.2 mm) with
solvent systems given in the text. Visualization of the spots was
effected by exposure to UV light and charring with a solution of
5% (v/v) sulfuric acid in EtOH containing 0.5% p-anisaldehyde.
Column chromatography was carried out with Silica Gel 60 (230–
400 mesh, Merck). Optical rotations were measured with a Perkin–
Elmer 343 digital polarimeter. Nuclear magnetic resonance (NMR)
spectra were recorded with a Bruker AC 200 or with a Bruker
AMX 500 instrument. Assignments of 1H and 13C resonances were
assisted by 2D 1H-COSY and HSQC experiments.
2-Propyl 6-O-Acetyl-3-deoxy-4-S-(2,3,5-tri-O-benzoyl-α-
D-arabino-
furanosyl)-4-thio-α- -threo-hexopyranosid-2-ulose (4): To a solution
D
of 1,2,3,5-tetra-O-benzoyl-β--arabinofuranose (1b; 140 mg,
0.25 mmol) in anhydrous acetonitrile (5 mL) was added thiourea
(21 mg, 0.276 mmol) and BF3·OEt2 (162 µL, 1.29 mmol). The mix-
Scheme 4.
Eur. J. Org. Chem. 2008, 540–547
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543

E. Repetto, C. Marino, M. L. Uhrig, O. Varela
FULL PAPER
ture was heated under reflux for 1 h at which point TLC (toluene/
EtOAc, 3:1) showed disappearance of the starting material and a
spot of Rf = 0. Evaporation of the solvent led to α-S-glycosyl iso-
thiourea 2 as a syrup. H NMR (500 MHz, [D6]DMSO): δ = 9.29,
9.17 (2 s, each 2 H, 2ϫNH2), 8.06–7.35 (m, 20 H, ArH), 6.67 (br.
J2Ј,3Ј = 5.1 Hz, 1 H, 2Ј-H), 5.52 (d, J1Ј,2Ј = 3.7 Hz, 1 H, 1Ј-H), 4.77
(m, J4,5 = 1.5 Hz, 1 H, 5-H), 4.74 (br. s, 1 H, 1-H), 4.71 (dd, J4Ј,5Јa
= 3.7 Hz, J5Јa,5Јb = 11.6 Hz, 1 H, 5Јa-H), 4.67 (m, 1 H, 4Ј-H), 4.58
(dd, J4Ј,5Јb = 4.5 Hz, J5Јa,5Јb = 11.6 Hz, 1 H, 5Јb-H), 4.27 (dd, J5,6a
= 6.8 Hz, J6a,6b = 11.5 Hz, 1 H, 6a-H), 4.24 (dd, J5,6b = 5.3 Hz,
1
s, 1 H, 1-H), 5.74 (br. s, 1 H, 2-H), 5.72 (d, J3,4 = 4.8 Hz, 1 H, 3- J6a,6b = 11.5 Hz, 1 H, 6b-H), 3.99 [m, J = 6.2 Hz, 1 H, (CH3)2-
H), 4.88 (m, J4,5 = 3.1 Hz, J4,5Ј = 4.4 Hz, 1 H, 4-H), 4.74 (dd, J4,5 CHO], 3.81 (m, 1 H, 4-H), 3.16 (dd, J3ax,4 = 4.7 Hz, J3ax,3eq
=
= 3.1 Hz, J5,5Ј = 12.3 Hz, 1 H, 5-H), 4.70 (dd, J4,5Ј = 4.4 Hz, J5,5Ј 15.2 Hz, 1 H, 3ax-H), 2.83 (dd, J3eq,4 = 2.0 Hz, J3ax,3eq = 15.2 Hz,
= 12.3 Hz, 1 H, 5Ј-H) ppm. 13C NMR (125.7 MHz, [D6]- 1 H, 3eq-H), 2.08 (s, 3 H, CH3CO), 1.17, 1.12 [2 d, J = 6.2 Hz, 6
DMSO): δ = 167.9 [SC(NH2)2], 167.1, 165.9, 165.4, 165.2 (PhCO), H, (CH3)2CHO] ppm. 13C NMR (125.7 MHz, CDCl3): δ = 198.2
135–128 (C-aromatic), 87.8 (C-1), 82.8, 81.8 (C-2, 4), 77.3 (C-3),
63.1 (C-5) ppm.
(C-2), 170.4 (CH3CO), 166.0, 165.2 (2 C, PhCO), 133.6, 133.5,
133.3, 129.8, 129.7, 128.5, 128.4 (C-aromatic), 97.9 (C-1), 84.2 (C-
1Ј), 80.4 (C-4Ј), 75.5 (C-2Ј), 72.6, 71.6 [C-3Ј, (CH3)2CHO], 68.4 (C-
5), 64.4, 64.3 (C-5Ј, 6), 44.8 (C-4), 42.7 (C-3), 23.2, 21.7 [(CH3)2-
CHO], 20.7 (CH3CO) ppm. Compound 8: 1H NMR (500 MHz,
CDCl3): δ = 8.09–7.30 (m, 15 H, ArH), 5.96 (d, J1Ј,2Ј = 6.0 Hz, 1
H, 1Ј-H), 5.72 (dd, J3Ј,4Ј = 4.6 Hz, J2Ј,3Ј = 6.4 Hz, 1 H, 3Ј-H), 5.65
(dd, J1Ј,2Ј = 6.0 Hz, J2Ј,3Ј = 6.4 Hz, 1 H, 2Ј-H), 4.78–4.71 (m, 4 H,
1-H, 4Ј-H, 5-H, 5Јa-H), 4.61 (dd, J4Ј,5Јb = 4.0 Hz, J5Јa,5Јb = 12.0 Hz,
1 H, 5Јb-H), 4.22 (dd, J5,6a = 6.6 Hz, J6a,6b = 11.3 Hz, 1 H, 6a-H),
4.18 (dd, J5,6b = 5.7 Hz, 1 H, 6b-H), 3.98 [m, J = 6.2 Hz, 1 H,
(CH3)2CHO], 3.63 (m, 1 H, 4-H), 3.23 (dd, J3ax,4 = 3.8 Hz, J3ax,3eq
= 14.8 Hz, 1 H, 3ax-H), 2.98 (dd, J3eq,4 = 2.0 Hz, 1 H, 3eq-H),
2.05 (s, 3 H, CH3CO), 1.26, 1.18, [2 d, J = 6.2 Hz, 6 H,
(CH3)2CHO] ppm. 13C NMR (125.7 MHz, CDCl3): δ = 199.5 (C-
2), 170.4 (CH3CO), 166.1, 165.6, 165.1 (PhCO), 133.5 (ϫ2), 133.3,
130.0, 129.9, 129.7, 128.6, 128.5, 128.4 (C-aromatic), 98.0 (C-1),
88.8 (C-1Ј), 79.0 (C-4Ј), 72.0 (C-2Ј), 71.7 [(CH3)2CHO], 70.9 (C-
3Ј), 68.5 (C-5), 64.3 (C-6), 63.5, (C-5Ј), 48.6 (C-4), 44.9 (C-3), 23.2,
21.8 [(CH3)2CHO], 20.7 (CH3CO) ppm.
The original mixture without any further treatment, was cooled
to –18 °C and 2-propyl 6-O-acetyl-2,3-dideoxy-α--glycero-hex-3-
enopyranosid-2-ulose (3; 47 mg, 0.21 mmol) was added. Upon ad-
dition of Et3N (289 µL, 2.08 mmol) the mixture was stirred at
–18 °C for 3 h. TLC (CH2Cl2/EtOAc, 15:1) revealed the presence
of a major product (Rf = 0.75) and a faint spot of unreacted enone
3 (Rf = 0.54). The mixture was concentrated, and the residue was
purified by flash chromatography (chloroform/EtOAc, 98:1) to give
syrupy thiodisaccharide 4 (85 mg, 57.3%) slightly contaminated
with 3. 1H NMR (500 MHz, CDCl3): δ = 8.10–7.73 (m, 15 H,
ArH), 5.64 (br. s, 1 H, 1Ј-H), 5.62 (d, J2Ј,3Ј ≈ 0 Hz, J3Ј,4Ј = 5.0 Hz,
1 H, 3Ј-H), 5.52 (br. s, 1 H, 2Ј-H), 4.84 (dd, J4Ј,5Јa = 3.0 Hz, J5Јa,5Јb
= 11.6 Hz, 1 H, 5Јa-H), 4.79–4.76 (m, 2 H, 4Ј-H, 5-H), 4.76 (br. s,
1 H, 1-H), 4.73 (dd, J4Ј,5Јb = 4.6 Hz, J5Јa,5Јb = 11.6 Hz, 1 H, 5Јb-
H), 4.39 (dd, J5,6a = 7.0 Hz, J6a,6b = 11.7 Hz, 1 H, 6a-H), 4.36 (dd,
J5,6b = 5.2 Hz, J6a,6b = 11.7 Hz, 1 H, 6b-H), 4.01 [m, J = 6.2 Hz, 1
H, (CH3)2CHO], 3.76 (m, 1 H, 4-H), 3.22 (dd, J3ax,3eq = 14.9 Hz,
J3ax,4 = 4.7 Hz, 1 H, 3ax-H), 2.94 (dd, J3eq,4 = 1.8 Hz, J3ax,3eq
=
14.9 Hz, 1 H, 3eq-H), 2.07 (s, 3 H, CH3CO), 1.28, 1.19 [2 d, J =
6.2 Hz, 6 H, (CH3)2CHO] ppm. 13C NMR (125.7 MHz, CDCl3): δ
= 199.3 (C-2), 170.5 (CH3CO), 166.1, 165.6, 165.4 (PhCO), 133.7,
133.1, 130.0, 129.9, 129.8 (ϫ2), 128.6, 128.5, 128.4 (C-aromatic),
98.0 (C-1), 89.6 (C-1Ј), 83.3 (C-2Ј), 81.0 (C-4Ј), 77.7 (C-3Ј), 71.7
[(CH3)2CHO], 68.5 (C-5), 64.4 (C-6), 63.2 (C-5Ј), 48.5 (C-4), 44.2
(C-3), 23.3, 21.8 [(CH3)2CHO], 20.7 (CH3CO) ppm.
Similar to 4, thiodisaccharides 7 and 8 appeared slightly contami-
nated with 3 after the column chromatography.
2-Propyl 6-O-Acetyl-3-deoxy-4-S-(2,3,5-tri-O-benzoyl-β-
D-xylofu-
ranosyl)-4-thio-α- -threo-hexopyranosid-2-ulose (11) and α-
D
D-Xylo-
furanosyl Analogue 12: Commercially available 1,2,3,5-tetra-O-ben-
zoyl-α--xylofuranose (9; 200 mg, 0.35 mmol), thiourea (30 mg,
0.395 mmol) and BF3·OEt2 (67 µL, 0.53 mmol) were combined
in anhydrous acetonitrile (7 mL) to yield S-glycosyl iso-
The procedure described above was also applied to 1,2,3,5-tetra-O-
benzoyl-α--arabinofuranose (1a) to afford 4 (93 mg, 62.7%).
1
thiourea 10. H NMR (500 MHz, [D6]DMSO): δ = 9.28–9.19 (2 s,
2-Propyl 6-O-Acetyl-3-deoxy-4-S-(2,3,5-tri-O-benzoyl-β-
ranosyl)-4-thio-α-D-threo-hexopyranosid-2-ulose (7) and α-
D
-ribofu-
each 2 H, 2ϫNH2), 8.10–7.48 (m, 20 H, ArH), 6.44 (br. s, 1 H, 1-
H), 6.02 (d, J3,4 = 4.6 Hz, 1 H, 3-H), 5.78 (br. s, 1 H, 2-H), 5.12
(q, J4,5 ≈ J4,5Ј = 5.0 Hz, 1 H, 4-H), 4.64 (m, 2 H, 5-H, 5Ј-H) ppm.
13C NMR (50 MHz, [D6]DMSO): δ = 167.7, 167.4, 165.7, 164.6 (2
C, PhCO + SC(NH2)2], 134.6–128.5 (C-aromatic), 86.0 (C-1), 80.8,
80.6 (C-2, 4), 75.0 (C-3), 62.5 (C-5) ppm.
D-Ribofu-
ranosyl Analogue 8: A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-
β--ribofuranose (5; 300 mg, 0.595 mmol), thiourea (50 mg,
0.658 mmol) and BF3·OEt2 (78 µL, 0.625 mmol) in anhydrous ace-
tonitrile (10 mL) was stirred under reflux for 1 h to afford S-glyco-
syl isothiourea derivative 6. 1H NMR (200 MHz, [D6]DMSO): δ =
9.27, 9.22 (2 s, each 2 H, 2ϫNH2), 8.07–7.45 (m, 15 H, ArH), 6.42
(d, J1,2 = 3.7 Hz, 1 H, 1-H), 5.94 (m, 2 H, 2-H, 3-H), 4.91 (m, J4,5
= 3.5 Hz, J3,4 = J4,5Ј = 4.0 Hz, 1 H, 4-H), 4.69 (dd, J4,5 = 3.5 Hz,
J5,5Ј = 11.9 Hz, 1 H, 5-H), 4.59 (dd, J4,5Ј = 4.0 Hz, J5,5Ј = 11.9 Hz,
1 H, 5Ј-H) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 166.8
[SC(NH2)2], 165.6, 164.9, 164.6 (PhCO), 134.4–128.2 (C-aromatic),
84.3 (C-1), 81.5, 74.3, 71.8 (C-2, C-3, C-4), 63.8 (C-5) ppm.
Compound 10 was treated with enone 3 (64 mg, 0.28 mmol) and
Et3N (350 µL, 2.52 mmol) at 0 °C to afford a 1.4:1 mixture of
thiodisaccharides 11/12. β--Xylofuranosyl isomer 11 was
partially purified by column chromatography (CHCl3/EtOAc,
85:1Ǟ70:1). Compound 11: 1H NMR (500 MHz, CDCl3): δ = 5.47
(d, J1Ј,2Ј = 1.4 Hz, 1 H, 1Јβ-H), 4.73 (br. s, 1 H, 1-H), 3.87 (m, 1
H, 4-H), 3.22 (dd, J3ax,4 = 4.9 Hz, J3ax,3eq = 15.2 Hz, 1 H, 3ax-H),
2.86 (dd, J3eq,4 = 1.8 Hz, J3ax,3eq = 15.2 Hz, 1 H, 3eq-H) ppm. 13C
An acetonitrile solution containing 6 was cooled to –18 °C and
enone 3 (100 mg, 0.439 mmol) and Et3N (220 µL, 1.58 mmol) were NMR (125.7 MHz, CDCl3): δ = 198.8 (C-2), 97.9 (C-1), 85.6 (C-
added. After 2.5 h, the mixture showed by TLC (CH2Cl2/EtOAc,
15:1) two main spots with Rf = 0.60 and 0.49. Purification by flash
chromatography (chloroform/EtOAc, 99:1) gave first less polar
product 7 (110 mg, 35.5%). The following fractions from the col-
umn afforded compound 8 (140 mg, 45.2%). Compound 7: 1H
NMR (500 MHz, CDCl3): δ = 8.08–7.32 (m, 15 H, ArH), 5.89 (dd,
J2Ј,3Ј = 5.1 Hz, J3Ј,4Ј = 6.0 Hz, 1 H, 3Ј-H), 5.69 (dd, J1Ј,2Ј = 3.7 Hz,
1Ј), 81.6, 79.8 (C-2Ј, 4Ј), 75.2 (C-3Ј), 45.3 (C-4), 42.6 (C-3) ppm.
1
Compound 12: H NMR (500 MHz, CDCl3): δ = 6.00 (d, J1Ј,2Ј
=
6.0 Hz, 1 H, 1Јα-H), 4.76 (br. s, 1 H, 1-H), 3.65 (m, 1 H, 4-H), 3.19
(dd, J3ax,4 = 4.7 Hz, J3ax,3eq = 14.9 Hz, 1 H, 3ax-H), 2.97 (dd, J3eq,4
= 1.8 Hz, J3ax,3eq = 14.9 Hz, 1 H, 3eq-H) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 97.9 (C-1), 88.2 (C-1Ј), 78.5 (C-4Ј), 61.8
(C-5Ј), 48.1 (C-4), 44.6 (C-3) ppm.
544
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 540–547

Thiodisaccharides with a Furanose Unit as the Nonreducing End
2-Propyl 6-O-Acetyl-3-deoxy-4-S-(2,3,5-tri-O-benzoyl-α-
D
-arabino-
-lyxo-hexopyranoside (13) and 4-Thio-α- -xylo
solution of thiodisaccharide (120 mg,
176–177 °C. [α]2D0 = +195.9 (c = 0.9, H2O). 1H NMR (500 MHz,
D2O): δ = 5.09 (d, J1Ј,2Ј = 4.7 Hz, 1 H, 1Ј-H), 4.88 (d, J1,2 = 3.7 Hz,
1 H, 1-H), 4.12 (ddd, J4,5 = 1.9 Hz, J5,6a ≈ J5,6b ≈ 6.1 Hz, 1 H, 5-
H), 4.00–3.96 (m, 2 H, 2-H, 4Ј-H), 3.95 (dd, J1Ј,2Ј = 4.7 Hz, J2Ј,3Ј
= 4.8 Hz, 1 H, 2Ј-H), 3.91 [m, J = 6.2 Hz, 1 H, (CH3)2CHO], 3.87
furanosyl)-4-thio-α-
Analogue 14: To
D
D
a
4
0.17 mmol) in THF (7 mL) was added NaBH4 (64 mg, 1.7 mmol),
and the mixture was stirred for 30 min at –18 °C. The solution was
neutralized with Dowex 50W (H+) resin, filtered, and concentrated.
The residue was dissolved in MeOH, and the solvent was evapo-
rated to remove boric acid. The procedure was repeated three times
to afford a syrup that showed two spots by TLC (hexane/EtOAc,
1:1) having Rf = 0.56 and 0.50. Column chromatography (hexane/
(dd, J2Ј,3Ј = 4.8 Hz, J3Ј,4Ј = 7.1 Hz, 1 H, 3Ј-H), 3.73 (dd, J4Ј,5Јa
=
3.0 Hz, J5Јa,5Јb = 12.5 Hz, 1 H, 5Јa-H), 3.64 (m, 2 H, 6a-H, 6b-H),
3.63 (dd, J4Ј,5Јb = 5.5 Hz, J5Јa,5Јb = 12.5 Hz, 1 H, 5Јb-H), 3.33 (m,
1 H, 4-H), 2.13 (ddd, J3ax,4 = 4.0 Hz, J3ax,3eq = 12.5 Hz, J2,3ax
12.8 Hz, 1 H, 3ax-H), 2.02 (ddd, J2,3eq ≈ J3eq,4 ≈ 3.9 Hz, J3ax,3eq
=
=
EtOAc, 70:30) of the mixture first afforded the less polar product. 12.5 Hz, 1 H, 3eq-H), 1.16, 1.08 [2 d, J = 6.2 Hz, 6 H, (CH3)2CHO]
Further purification through a dry column of silica gel (hexane/
EtOAc, 1:1) afforded syrupy thiodisaccharide 13 (12.0 mg, 10.0%)
and foamy 14 (61.0 mg, 50.7%). Compound 13: [α]2D0 = +80.7 (c =
ppm. 13C NMR (125.7 MHz, D2O): δ = 96.0 (C-1), 89.7 (C-1Ј),
82.4 (C-4Ј), 81.6 (C-2Ј), 75.8 (C-3Ј), 70.6, 70.5 [C-5, (CH3)2CHO],
64.1 (C-2), 62.5 (C-6), 60.7 (C-5Ј), 44.7 (C-4), 33.8 (C-3), 22.3, 20.5
1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 8.09–7.31 (m, 15 [(CH3)2CHO] ppm. C14H26O8S (354.41): calcd. C 47.44, H 7.39, S
H, ArH), 5.66 (s, 1 H, 1Ј-H), 5.64 (d, J3Ј,4Ј = 4.4 Hz, 1 H, 3Ј-H),
5.56 (s, 1 H, 2Ј-H), 4.89 (br. s, 1 H, 1-H), 4.84 (dd, J4Ј,5Јa = 3.5 Hz,
J5Јa,5Јb = 11.1 Hz, 1 H, 5Јa-H), 4.81 (m, 1 H, 4Ј-H), 4.73 (dd, J4Ј,5Јb
= 4.3 Hz, J5Јa,5Јb = 1.1 Hz, 1 H, 5Јb-H), 4.41 (ddd, J4,5 = 2.4 Hz,
J5,6b = 4.6 Hz, J5,6a = 7.5 Hz, 1 H, 5-H), 4.37 (dd, J5,6a = 7.5 Hz,
9.06; found C 47.32, H 7.45, S 9.23.
2-Propyl 6-O-Acetyl-3-deoxy-4-S-(2,3,5-tri-O-benzoyl-β-
furanosyl)-4-thio-α-D-lyxo-hexopyranoside (16) and 4-Thio-α-D-xylo
D
-ribo-
Analogue 17: Compound 7 (95 mg, 0.135 mmol) was treated with
NaBH4 (70 mg, 1.85 mmol) as described for 4. After 30 min, moni-
toring of the reaction mixture by TLC (hexane/EtOAc, 1:1) re-
vealed two main spots having Rf = 0.61 and 0.54. The mixture was
subjected to column chromatography (hexane/EtOAc, 70:30). The
less polar compound was repurified through a dry column of silica
gel (hexane/EtOAc, 1:1) to afford pure 16 (6 mg, 6.3%) and major
thiodisaccharide 17 (36 mg, 37.7%). From intermediate fractions
of the column, a mixture of 16 and 17 was obtained (33 mg, 83.6%
overall yield). Compound 16: [α]2D0 = +15.7 (c = 0.8, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 8.09–7.33 (m, 15 H, ArH), 5.89 (dd,
J2Ј,3Ј = 5.0 Hz, J3Ј,4Ј = 5.9 Hz, 1 H, 3Ј-H), 5.73 (dd, J1Ј,2Ј = 3.6 Hz,
J2Ј,3Ј = 5.0 Hz, 1 H, 2Ј-H), 5.64 (d, J1Ј,2Ј = 3.6 Hz, 1 H, 1Ј-H), 4.88
(br. s, 1 H, 1-H), 4.73 (dd, J4Ј,5Јa = 3.9 Hz, J5Јa,5Јb = 11.2 Hz, 1 H,
J6a,6b = 11.1 Hz, 1 H, 6a-H), 4.31 (dd, J5,6b = 4.6 Hz, J6a,6b
=
11.1 Hz, 1 H, 6b-H), 3.92 [m, J = 6.3 Hz, 1 H, (CH3)2CHO], 3.62
(m, 1 H, 2-H), 3.48 (d, J = 9.6 Hz, 1 H, OH), 3.32 (br. s, 1 H, 4-
H), 2.41 (ddd, J2,3a ≈ J3a,4 = 3.0 Hz, J3a,3b = 15.0 Hz, 1 H, 3a-H),
2.35 (ddd, J2,3b ≈ J3b,4 = 3.9 Hz, J3a,3b = 15.0 Hz, 1 H, 3b-H), 1.22,
1.16 [2 d, J = 6.3 Hz, 6 H, (CH3)2CHO] ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 170.6 (CH3CO), 166.1, 165.6 (2 C,
PhCO), 133.8, 133.7, 133.1, 130.0, 129.9, 129.8, 128.8, 128.6, 128.4
(C-aromatic), 98.9 (C-1), 89.7 (C-1Ј), 83.2 (C-2Ј), 81.5 (C-4Ј), 77.8
(C-3Ј), 69.5 [(CH3)2 CHO], 68.0 (C-5), 67.7 (C-2), 65.0 (C-6), 63.3
(C-5Ј), 42.4 (C-4), 31.8 (C-3), 23.2, 21.5 [(CH3)2CHO], 20.8
(CH3CO) ppm. C37H40O12S (708.78): calcd. C 62.70, H 5.69, S
4.52; found C 62.82, H 5.59, S 4.63. Compound 14: [α]2D0 = +73.1
1
5Јa-H), 4.71 (m, 1 H, 4Ј-H), 4.58 (dd, J4Ј,5Јb = 4.0 Hz, J5Јa,5Јb
11.2 Hz, 1 H, 5Јb-H), 4.41 (m, 1 H, 5-H), 4.26 (dd, J5,6a = 7.9 Hz,
J6a,6b = 11.6 Hz, 1 H, 6a-H), 4.16 (dd, J5,6b = 4.5 Hz, J6a,6b
=
(c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 8.11–7.30 (m,
15 H, ArH), 5.61 (d, J3Ј,4Ј = 5.3 Hz, 1 H, 3Ј-H), 5.60 (s, 1 H, 1Ј-
H), 5.55 (s, 1 H, 2Ј-H), 4.92 (d, J1,2 = 3.8 Hz, 1 H, 1-H), 4.84 (dd,
J4Ј,5Јa = 3.0 Hz, J5Јa,5Јb = 11.6 Hz, 1 H, 5Јa-H), 4.77 (m, 1 H, 4Ј-
H), 4.72 (dd, J4Ј,5Јb = 5.0 Hz, J5Јa,5Јb = 11.6 Hz, 1 H, 5Јb-H), 4.32
(dd, J5,6a = 8.7 Hz, J6a,6b = 12.2 Hz, 1 H, 6a-H), 4.27 (m, 1 H, 5-
H), 4.26 (dd, J5,6b = 4.8 Hz, J6a,6b = 12.2 Hz, 1 H, 6b-H), 4.02 (m,
1 H, 2-H), 3.95 [m, J = 6.2 Hz, (CH3)2CHO], 3.38 (br. s, 1 H, 4-
H), 2.29 (ddd, J2,3eq ≈ J3eq,4 ≈ 3.9 Hz, J3ax,3eq = 12.8 Hz, 1 H, 3eq-
H), 2.09 (ddd, J3ax,4 = 3.7 Hz, J2,3ax = J3ax,3eq = 12.8 Hz, 1 H, 3ax-
H), 2.02 (s, 3 H, CH3CO), 1.26, 1.19 [2 d, 6 H, (CH3)2CHO] ppm.
13C NMR (125.7 MHz, CDCl3): δ = 170.6 (CH3CO), 166.2, 165.4
(PhCO), 133.7, 133.6, 133.1, 130.0, 129.9, 128.9, 128.6, 128.5, 128.4
(C-aromatic), 96.8 (C-1), 90.0 (C-1Ј), 83.2 (C-2Ј), 81.2 (C-4Ј), 78.0
(C-3Ј), 70.9 [(CH3)2CHO], 67.8 (C-5), 64.9 (C-6), 64.6 (C-2), 63.4
(C-5Ј), 45.7 (C-4), 35.7 (C-3), 23.2, 22.0 [(CH3)2CHO], 20.8
(CH3CO) ppm. C37H40O12S (708.78): calcd. C 62.70, H 5.69, S
4.52; found C 62.64, H 5.60, S 4.62.
=
11.6 Hz, 1 H, 6b-H), 3.94 [m, J = 6.2 Hz, 1 H, (CH3)2CHO], 3.62
(m, 1 H, 2-H), 3.54 (d, J = 10.3 Hz, 1 H, 2-HO), 3.41 (m, 1 H, 4-
H), 2.30 (m, 2 H, 3a-H, 3b-H), 2.05 (s, 3 H, CH3CO), 1.23, 1.18 [2
d, J = 6.2 Hz, 6 H, (CH3)2CHO] ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 170.5 (CH3CO), 166.1, 165.1 ( ϫ 2, PhCO),
133.6, 133.5, 129.9, 129.8, 128.5, 128.4 (C-aromatic), 98.9 (C-1),
84.5 (C-1Ј), 80.4 (C-4Ј), 75.6 (C-2Ј), 72.6 (C-3Ј), 69.4
[(CH3)2CHO], 67.9 (C-2), 67.6 (C-5), 64.9 (C-6), 64.3 (C-5Ј), 39.3
(C-4), 29.8 (C-3), 23.1, 21.5 [(CH3)2CHO], 20.7 (CH3CO) ppm.
C37H40O12S (708.78): calcd. C 62.70, H 5.69, S 4.52; found C 62.39,
H 5.77, S 4.43. Compound 17: [α]2D0 = +37.5 (c = 0.95, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 8.09–7.33 (m, 15 H, ArH), 5.87 (dd,
J2Ј,3Ј = 5.1 Hz, J3Ј,4Ј = 5.8 Hz, 1 H, 3Ј-H), 5.69 (dd, J1Ј,2Ј = 3.7 Hz,
J2Ј,3Ј = 5.1 Hz, 1 H, 2Ј-H), 5.51 (d, J1Ј,2Ј = 3.7 Hz, 1 H, 1Ј-H), 4.89
(d, J1,2 = 3.8 Hz, 1 H, 1-H), 4.71 (dd, J4Ј,5Јa = 4.0 Hz, J5Јa,5Јb
11.2 Hz, 1 H, 5Јa-H), 4.68 (ddd, J4Ј,5Јa = 4.0 Hz, J4Ј,5Јb = 4.2 Hz,
-xylo- J3Ј,4Ј = 5.8 Hz, 1 H, 4Ј-H), 4.59 (dd, J4Ј,5Јb = 4.2 Hz, J5Јa,5Јb
11.2 Hz, 1 H, 5Јb-H), 4.25 (ddd, J4,5 = 2.0 Hz, J = 5.0 Hz, J =
6.9 Hz, 1 H, 5-H), 4.18 (m, 2 H, 6a-H, 6b-H), 4.02 (ddd, J1,2
=
2-Propyl 3-Deoxy-4-S-(α-
D
-arabinofuranosyl)-4-thio-α-
D
=
hexopyranoside (15): Thiodisaccharide 14 (60 mg, 0.085 mmol) was
suspended in a solution of MeOH/Et3N/H2O (3:1:3; 8.5 mL) and
stirred at room temperature. After 3 h, TLC (hexane/EtOAc, 1:1)
showed a spot of Rf = 0.0 (UV inactive) and no starting 14 (Rf =
0.50). The mixture was concentrated, and the residue, dissolved in
water (1 mL), was eluted through a column filled with Dowex MR-
3C mixed-bed ion-exchange resin. The deionized solution was con-
centrated, and the free thiodisaccharide was purified by dissolution
in water (1 mL) and filtered through an octadecyl C18 minicolumn
(Amprep, Amersham Biosciences). Evaporation of the solvent af-
forded crystalline free thiodisaccharide 15 (21 mg, 70.6%). M.p.
=
3.8 Hz, J2,3eq = 4.3 Hz, J2,3ax = 11.5 Hz, 1 H, 2-H), 3.93 [m, J =
6.2 Hz, 1 H, (CH3)2CHO], 3.42 (br. s, 1 H, 4-H), 2.24 (ddd, J3eq,4
= 3.5 Hz, J2,3eq = 4.3 Hz, J3ax,3eq = 13.0 Hz, 1 H, 3eq-H), 2.01 (m,
4 H, 3ax-H, CH3CO), 1.21, 1.18, [2 d, J = 6.2 Hz, 6 H, (CH3)2-
CHO] ppm. 13C NMR (125.7 MHz, CDCl3): δ = 170.5 (CH3CO),
166.1, 165.1 (PhCO), 133.6, 133.5, 133.1, 129.8, 128.5, 128.4 (C-
aromatic), 96.8 (C-1), 85.4 (C-1Ј), 80.2 (C-4Ј), 75.8 (C-2Ј), 72.8,
70.8 [C-3Ј, (CH3)2CHO], 67.8 (C-2), 65.1 (C-6), 64.5 (C-5), 64.2
(C-5Ј), 43.2 (C-4), 34.2 (C-3), 23.2, 22.0 [(CH3)2CHO], 20.8
Eur. J. Org. Chem. 2008, 540–547
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
545

E. Repetto, C. Marino, M. L. Uhrig, O. Varela
FULL PAPER
(CH3CO) ppm. C37H40O12S (708.78): calcd. C 62.70, H 5.69, S
4.52; found C 62.89, H 5.65, S 4.43.
idue was purified by column chromatography (toluene/EtOAc,
95:5) to afford syrupy 21 (45 mg, 51.7%). [α]2D0 = +22.6 (c = 0.8,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 8.09–7.28 (m, 15 H,
ArH), 6.11 (t, J2,3 ≈ J3,4 = 10 Hz, 1 H, 3-H), 5.87 (t, J2Ј,3Ј ≈ J3Ј,4Ј
= 5.5 Hz, 1 H, 3Ј-H), 5.73 (dd, J1Ј,2Ј = 3.3 Hz, J2Ј,3Ј = 5.5 Hz, 1 H,
2Ј-H), 5.70 (d, J1Ј,2Ј = 3.3 Hz, 1 H, 1Ј-H), 5.45 (t, J4,5 = 9.8 Hz, 1
H, 4-H), 5.23 (dd, J1,2 = 3.6 Hz, J2,3 = 10.0 Hz, 1 H, 2-H), 5.19 (d,
J1,2 = 3.6 Hz, 1 H, 1-H), 4.70 (m, 2 H, 4Ј-H, 5Јa-H), 4.54 (dd, J4Ј,5Јb
= 5.5 Hz, J5Јa,5Јb = 12.9 Hz, 1 H, 5Јb-H), 4.26 (ddd, J5,6b = 2.2 Hz,
J5,6a = 9.5 Hz, J4,5 = 9.8 Hz, 1 H, 5-H), 3.45 (s, 3 H, CH3O), 3.06
2-Propyl 3-Deoxy-4-S-(β-D-ribofuranosyl)-4-thio-α-D-xylo-hexo-
pyranoside (18): Compound 17 (65 mg, 0.092 mmol) was subjected
to the same O-deacylation procedure as that described for 14 to
afford crystalline 18 (22 mg, 65.2%). M.p. 149–151 °C. [α]2D0 = +3.5
1
(c = 0.9, H2O). H NMR (500 MHz, CDCl3): δ = 5.04 (d, J1Ј,2Ј
=
4.8 Hz, 1 H, 1Ј-H), 4.88 (d, J1,2 = 3.7 Hz, 1 H, 1-H), 4.16 (ddd, J
= 2.0 Hz, J = 5.5 Hz, J = 6.8 Hz, 1 H, 5-H), 4.12 (dd, J2Ј.3Ј ≈ J3Ј,4Ј
≈ 5.0 Hz, 1 H, 3Ј-H), 4.02 (ddd, J2,3eq = 4.3 Hz, J2,3ax = 12.0 Hz,
J1,2 = 3.7 Hz, 1 H, 2-H), 3.99 (dd, J1Ј,2Ј = 4.8 Hz, J2Ј,3Ј = 5.0 Hz,
(dd, J5,6a = 9.5 Hz, J6a,6b = 14.4 Hz, 1 H, 6a-H), 2.91 (dd, J5,6b
=
2.2 Hz, J6a,6b = 14.4 Hz, 1 H, 6b-H) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 166.1, 165.8, 165.3 (PhCO), 133.5, 133.3, 133.1, 133.0,
129.8, 129.7, 129.6, 128.4, 128.2 (C-aromatic), 96.8 (C-1), 87.0 (C-
1Ј), 79.9 (C-4Ј), 75.7 (C-2Ј), 72.5 (C-3Ј), 72.2 (C-4), 72.1 (C-2), 70.8
(C-5), 70.3 (C-3), 65.0 (C-5Ј), 56.6 (CH3O), 32.6 (C-6) ppm.
C54H46O15S (967.01): calcd. C 67.07, H 4.79, S 3.31; found C 66.89,
H 4.89, S 3.25.
1 H, 2Ј-H), 3.92 (ddd, J4Ј,5Јa = 3.6 Hz, J3Ј,4Ј = 5.0 Hz, J4Ј,5Јb
=
5.8 Hz, 1 H, 4Ј-H), 3.91 [m, J = 6.2 Hz, 1 H, (CH3)2CHO], 3.67
(dd, J4Ј,5Јa = 3.6 Hz, J5Јa,5Јb = 12.4 Hz, 1 H, 5Јa-H), 3.63–3.60 (m,
2 H, 6a-H, 6b-H), 3.58 (dd, J4Ј,5Јb = 5.8 Hz, J5Јa,5Јb = 12.4 Hz, 1
H, 5Јb-H), 3.34 (m, 1 H, 4-H), 2.08 (ddd, J2,3ax = 12.0 Hz, J3ax,4
=
3.6 Hz, J3ax,3eq = 13.1 Hz, 1 H, 3ax-H), 2.00 (ddd, J3eq,4 = 3.5 Hz,
J2,3eq = 4.3 Hz, J3ax,3eq = 13.1 Hz, 1 H, 3eq-H), 1.16, 1.09 [2 d, J
= 6.2 Hz, 6 H, (CH3)2CHO] ppm. 13C NMR (125.7 MHz, CDCl3):
δ = 96.1 (C-1), 86.6 (C-1Ј), 84.5 (C-4Ј), 75.2 (C-2Ј), 71.1 (C-3Ј),
70.5 [(CH3)2CHO], 70.3 (C-5), 64.0 (C-2), 62.6 (C-6), 62.1 (C-5Ј),
42.9 (C-4), 32.2 (C-3), 22.4, 20.5 [(CH3)2CHO] ppm. C14H26O8S
(354.41): calcd. C 47.44, H 7.39, S 9.06; found C 47.33, H 7.41, S
9.19.
1,2:3,4-Di-O-isopropylidene-6-S-(2,3,5-tri-O-benzoyl-β-
D-ribo-
furanosyl)-6-thio-α- -galactopyranose (23): The procedure de-
D
scribed above was followed, starting from 5 (95 mg, 0.188 mmol)
and 1,2:3,4-di-O-isopropylidene-4-thio--galactose[25] (22; 78 mg,
0.28 mmol). Purification by column chromatography (toluene/
EtOAc, 97:3) gave compound 23 (53 mg, 39.1%). [α]2D0 = –48.5 (c
1
= 0.9, CHCl3). H NMR (500 MHz, CDCl3): δ = 8.10–7.16 (m, 15
2-Propyl 6-O-Acetyl-3-deoxy-4-S-(2,3,5-tri-O-benzoyl-α-
D-ribo-
H, ArH), 5.90 (dd, J2Ј,3Ј ≈ J3Ј,4Ј = 5.3 Hz, 1 H, 3Ј-H), 5.71 (dd,
J1Ј,2Ј = 3.9 Hz, J2Ј,3Ј = 5.3 Hz, 1 H, 2Ј-H), 5.61 (d, J1Ј,2Ј = 3.9 Hz,
1 H, 1Ј-H), 5.52 (d, J1,2 = 5.0 Hz, 1 H, 1-H), 4.69 (dd, J4Ј5Јa = 3.8,
furanosyl)-4-thio-α- -xylo-hexopyranoside (19): The reduction of 8
D
(45 mg, 0.064 mmol) with NaBH4 was performed as described for
analogue 7. Purification of the reaction mixture by column
chromatography (hexane/EtOAc, 70:30) gave 19 (29 mg, 64%) as
the major product. [α]2D0 = +93.2 (c = 0.6, CHCl3). 1H NMR
J5Јa,5Јb = 11.1 Hz, 1 H, 5Јa-H), 4.66 (ddd, J4Ј,5Јa = 3.8 Hz, J4Ј,5Јb
=
4.1 Hz, J3Ј,4Ј = 5.3 Hz, 1 H, 4Ј-H), 4.61 (dd, J4Ј,5Јb = 4.1 Hz, J5Јa,5Јb
= 11.1 Hz, 1 H, 5Јb-H), 4.58 (dd, J2,3 = 2.5 Hz, J3,4 = 7.8 Hz,1 H,
3-H), 4.31–4.38 (m, 2 H, 2-H, 4-H), 3.95 (ddd, J4,5 = 1.4 Hz, J5,6b
= 6.2 Hz, J5,6a = 7.3 Hz, 1 H, 5-H), 3.07 (dd, J5,6a = 7.3 Hz, J6a,6b
= 13.7 Hz, 1 H, 6a-H), 2.90 (dd, J5,6b = 6.2 Hz, J6a,6b = 13.7 Hz, 1
H, 6b-H), 1.49, 1.43, 1.31, 1.30 [4 s, 12 H, 2ϫ(CH3)2C] ppm. 13C
NMR (125.7 MHz, CDCl3): δ = 165.2, 165.1 (ϫ2, PhCO), 133.4,
133.1, 129.8, 129.7, 128.4, 128.3 (C-aromatic), 109.3, 108.6 [(CH3)2-
C], 96.5 (C-1), 86.3 (C-1Ј), 80.0 (C-4Ј), 75.7 (C-2Ј), 72.6 (C-3Ј),
71.5, 70.5 (C-2, C-4), 70.8 (C-3), 68.4 (C-5), 64.5 (C-5Ј), 30.5 (C-6),
26.0, 25.9, 24.9, 24.4 [(CH3)2C] ppm. C38H40O12S (720.79): calcd. C
63.32, H 5.59, S 4.45; found C 63.15, H 5.66, S 4.37.
(500 MHz, CDCl3): δ = 8.08–7.30 (m, 15 H, ArH), 5.93 (d, J1Ј,2Ј
=
6.0 Hz, 1 H, 1Ј-H), 5.74 (dd, J2Ј,3Ј = 6.6 Hz, J3Ј,4Ј = 4.3 Hz, 1 H,
3Ј-H), 5.63 (t, J1Ј,2Ј = 6.0 Hz, 1 H, 2Ј-H), 4.90 (d, J1,2 = 3.8 Hz, 1
H, 1-H), 4.76 (br. s, 1 H, 4Ј-H), 4.75 (dd, J5Јa,5Јb = 12.8 Hz, J4,5Јa
= 3.1 Hz, 1 H, 5Јa-H), 4.63 (dd, J4,5Јb = 4.8 Hz, J5Јa,5Јb = 12.8 Hz,
1 H, 5Јb-H), 4.22 (ddd, J4,5 = 1.7 Hz, J5,6b = 5.5 Hz, J5,6a = 7.0 Hz,
1 H, 5-H), 4.13 (dd, J6a,6b = 11.4 Hz, 1 H, 6a-H), 4.08 (dd, J5,6b
=
5.5 Hz, J6a,6b = 11.4 Hz, 1 H, 6b-H), 4.03 (m, 1 H, 2-H), 3.92 [m,
J = 6.2 Hz, 1 H, (CH3)2CHO], 3.28 (br. s, 1 H, 4-H), 2.34 (ddd,
J2,3eq = 3.8 Hz, J3eq,4 = 3.8 Hz, J3eq,3ax = 12.5 Hz, 1 H, 3eq-H),
2.10 (ddd, J3ax,4 = 3.6 Hz, J2,3ax = 12.0 Hz, J3ax,3eq = 12.5 Hz, 1 H,
3ax-H), 2.03 (s, 3 H, CH3CO), 1.86 (d, J2,OH = 12.0 Hz, 1 H, HO),
1.24, 1.81 [2 d, J = 6.2 Hz, 6 H, (CH3)2CHO] ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 170.5 (CH3CO), 166.1, 165.1, 165.2
(PhCO), 151.0, 136.0, 133.5, 133.3, 129.9, 129.7, 129.5, 129.0,
128.8, 128.5, 128.4, 127.8 (C-aromatic), 96.8 (C-1), 89.2 (C-1Ј), 79.0
(C-4Ј), 72.2 (C-2Ј), 71.2 (C-3Ј), 70.9 [(CH3)2CHO], 67.8 (C-5), 64.7
(C-6), 63.6 (C-5Ј), 60.4 (C-2), 46.1 (C-4), 35.2 (C-3), 23.2, 21.9
[(CH3)2CHO], 20.7 (CH3CO) ppm. C37H40O12S (708.78): calcd. C
62.70, H 5.69, S 4.52; found C 62.79, H 5.81, S 4.42.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for precursors, intermediates, and
thiodisaccharide final products.
Acknowledgments
Support of our work by the University of Buenos Aires (project
X059), the National Research Council of Argentina (CONICET,
project PIP 5011) and the National Agency for Promotion of Sci-
ence and Technology (ANPCyT, project 13922) is gratefully ac-
knowledged. O. V., C. M., and M. L. U. are Research Members of
CONICET.
Methyl 2,3,4-Tri-O-benzoyl-6-S-(2,3,5-tri-O-benzoyl-β-
D-ribo-
furanosyl)-6-thio-α- -glucopyranose (21): To a solution of MoO2Cl2
D
(0.9 mg, 0.004 mmol) in anhydrous CH2Cl2 (0.1 mL) was added a
solution of compound 5 (45 mg, 0.09 mmol) in CH2Cl2 (0.3 mL).
The reaction mixture was flushed with Ar and stirred at room tem-
perature for 10 min. Methyl 2,3.4-tri-O-benzoyl-6-thio--glucopyr-
anoside[23] (20; 70 mg, 0.134 mmol) dissolved in CH2Cl2 (0.2 mL)
was added. The solution immediately turned deep blue and grad-
ually changed to yellowish brown. After 2 h, TLC (toluene/EtOAc,
9:1) showed a main spot of Rf = 0.56. The reaction was quenched
with saturated aqueous NaCO3H, and the organic layer was sepa-
rated, washed with brine, dried, filtered, and concentrated. The res-
[1] H. Driguez, ChemBioChem 2001, 2, 311–318.
[2] H. Driguez, Top. Curr. Chem. 1997, 187, 85–116.
[3] F. Nicotra, Top. Curr. Chem. 1997, 187, 55–83.
[4] L. Szilágyi, O. Varela, Curr. Org. Chem. 2006, 10, 1745–1770.
[5] K. Pachamuthu, R. R. Schmidt, Chem. Rev. 2006, 106, 160–
187.
[6] W. B. Turnbull, R. A. Field, J. Chem. Soc. Perkin Trans. 1 2000,
1859–1866.
546
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 540–547

Thiodisaccharides with a Furanose Unit as the Nonreducing End
[7] J. Buckingham, J. A. Brazier, J. Fisher, R. Cosstick, Carbohydr.
Res. 2007, 342, 16–22.
[8] K. D. Randell, B. D. Johnston, E. E. Lee, B. M. Pinto, Tetrahe-
dron: Asymmetry 2000, 11, 207–222.
[9] Z. Minic, C.-T. Do, C. Rihouey, H. Morin, P. Lerouge, L. Jou-
anin, J. Exp. Bot. 2006, 57, 2339–2351.
[10] J. B. Houseknecht, T. L. Lowary, Curr. Opin. Chem. Biol. 2001,
5, 677–682.
[11] G. Lopez, R. Daniellou, M. O’Donohue, V. Ferrières, C. Nug-
ier-Chauvin, Bioorg. Med. Chem. Lett. 2007, 17, 434–438.
[12] M. L. Uhrig, V. E. Manzano, O. Varela, Eur. J. Org. Chem.
2006, 162–168.
[13] C. Marino, K. Mariño, L. Miletti, M. J. Manso Alves, W. Colli,
R. M. Lederkremer, Glycobiology 1998, 8, 901–904.
[14] M. L. Uhrig, L. Szilágyi, K. E. Kovér, O. Varela, Carbohydr.
Res. 2007, 342, 1841–1849.
[15] a) Z. J. Witczak, J. Sun, R. Mielguj, Bioorg. Med. Chem. Lett.
1995, 5, 2169–2174; b) Z. J. Witczak, R. Chhabra, H. Chen,
X.-Q. Xie, Carbohydr. Res. 1997, 301, 167–175; c) Z. J. Witczak,
P. Kaplon, M. Kolodziej, Monatsh. Chem. 2002, 133, 521–530;
d) Z. J. Witczak, P. Kaplon, P. M. Dey, Carbohydr. Res. 2003,
338, 11–18.
[17]
[18]
a) D. Horton, Methods Carbohydr. Chem. 1963, 2, 433–437; b)
D. Horton, M. L. Wolfrom, J. Org. Chem. 1962, 27, 1794–1800.
a) F. M. Ibatullin, S. I. Selivanov, A. G. Shavva, Synthesis 2001,
3, 419–422; b) F. M. Ibatullin, K. A. Shabalin, J. V. Jänis, A. G.
Shavva, Tetrahedron Lett. 2003, 44, 7961–7964.
L. Gandolfi-Donadío, C. Gallo-Rodriguez, R. M. Leder-
kremer, Can. J. Chem. 2006, 84, 486–491.
R. R. Gadikota, C. S. Callam, T. Wagner, B. Del Fraino, T. L.
Lowary, J. Am. Chem. Soc. 2003, 125, 4155–4165.
G. L. Szekeres, T. J. Bardos, J. Med. Chem. 1972, 15, 1333–
1334.
H. Rosemeyer, G. Tóth, B. Golankiewicz, Z. Kazimierczuk, W.
Bourgeois, U. Kretschmer, H.-P. Muth, F. Seela, J. Org. Chem.
1990, 55, 5784–5790.
B. D. Sherry, R. N. Loy, F. D. Toste, J. Am. Chem. Soc. 2004,
126, 4510–4511.
[19]
[20]
[21]
[22]
[23]
[24]
[25]
S.-S. Weng, Y.-D. Lin, C.-T. Chen, Org. Lett. 2006, 8, 5633–
5636.
M. A. Martins Alho, N. B. D’Accorso, I. M. E. Thiel, J. Hetero-
cycl. Chem. 1996, 33, 1339–1343.
[16] B. Becker, J. Thimm, J. Thiem, J. Carbohydr. Chem. 1996, 15,
Received: September 14, 2007
Published Online: November 27, 2007
1179–1181.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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