Thio-sugars. Part 5: From D-glucal to 3-deoxy-(1→2)-2-S-thiodisaccharides through isolevoglucosenone-a simple approach

Article abstract of DOI:10.1016/S0957-4166(99)00567-4

A new synthesis of isolevoglucosenone and its stereoselective functionalization into 3-deoxy-(1-2)-2-S-thiodisaccharides is described. The base-catalyzed conjugate addition of 1-thiosugars to isolevoglucosenone followed by the reduction of the C-4 keto function constitute a new two-step general approach to these classes of biologically important thio-sugars. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00567-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 519–532
Thio-sugars. Part 5: From D-glucal to 3-deoxy-(1→2)-
2
-S-thiodisaccharides through isolevoglucosenone — a simple
approach
∗
Zbigniew J. Witczak, Hong Chen and Peter Kaplon
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 372 Fairfield Rd. U-92, Storrs, CT
0
6269-2092, USA
Received 16 November 1999; accepted 8 December 1999
Abstract
A new synthesis of isolevoglucosenone and its stereoselective functionalization into 3-deoxy-(1-2)-2-S-
thiodisaccharides is described. The base-catalyzed conjugate addition of 1-thiosugars to isolevoglucosenone
followed by the reduction of the C-4 keto function constitute a new two-step general approach to these classes
of biologically important thio-sugars. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
1,2
In our efforts towards preparing thiodisaccharides, we employed enones 1 and 2. Both enones,
1
–4
levoglucosenone
(1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose, 1) and isomeric
5
–13
isolevoglucosenone
(1,6-anhydro-2,3-dideoxy-β-D-glycero-hex-2-enopyranos-4-ulose, 2), are, syn-
thetically, extremely attractive versatile chiral building blocks because of their high functionality and
conformational bicyclic rigidity, as depicted in Fig. 1.
The 1,6-anhydro bridge in both enones 1 and 2 eliminates the need for protecting groups at the
anomeric carbon and the C-6-OH. Moreover, the bridge fixes the conformation of the system and
sterically hinders the β-D-face of both molecules. Therefore, both enones have already been used in
1
0,11
the synthesis of various natural products and their intermediates.
However, isolevoglucosenone 2
is considerably less accessible than levoglucosenone 1 and relatively unstable,13 decomposing over
several months while in storage at −25°C. Levoglucosenone 1 was also used for the synthesis of
13
isolevoglucosenone 2 in ca. ∼25% overall yield.
As our need for larger quantities of enones 1 and 2 increased, we have been constantly exploring
methods that would make them more readily available for exploratory studies and multistep syntheses.
∗
Corresponding author. Fax: (860)-742-2400; e-mail: zwitczak@usa.net
0
957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00567-4
tetasy 3201

Fig. 1. (a) 1,6-Anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose (levoglucosenone); (b) 1,6-anhydro-2,3-dideoxy-β-D-glycero-hex-3-enopyranos-
-ulose (isolevoglucosenone)
4

Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
521
Thus, a convenient and efficient synthetic approach to isolevoglucosenone 2 is extremely important and
in demand.
5
The pioneering work of Achmatowicz et al. on the versatility of furfuryl alcohol and its conversion
to various enones, including a racemic mixture of isolevoglucosenone 2, was the first report of the
6
–9
preparation of isolevoglucosenone and other racemic 2,3-dideoxy-DL-hex-2-enopyranos-4-uloses.
1
0,11
Recently, Ogasawara et al.
developed a new approach to both enones 1 and 2 and their enan-
tiomers, exploring the utility of the non-carbohydrate precursor 2-vinylfuran. Köll and co-workers
1
2
synthesized isolevoglucosenone from levoglucosenone and from 1,6-anhydro-2,3-isopropylidene-β-D-
1
3
mannopyranose. Furneaux and co-workers reported the synthesis of isolevoglucosenone 2 directly
from levoglucosenone 1 in a five-step sequence. Through the rearrangement of 3-deoxy-1,2:5,6-di-
O-isopropylidene-α-D-erythro-hex-3-enofuranose, Horton and co-workers1
4,15
reported a completely
different and good yielding approach to isolevoglucosenone. Although overall yields in all of these
methods were acceptable, synthesis usually required a large number of steps and the use of air-sensitive
reagents such as sodium hydride and aluminum chloride (AlCl ) on a rather large scale.
3
2. Results and discussion
Studying the formation of the 1,6-anhydro ring, Oberdorfer and co-workers16,17 recently reported a
novel rearrangement of unprotected D-glucal 3 to allyl alcohol 4 under anhydrous conditions and in
the presence of anhydrous copper sulfate and molecular sieves. The fact that allyl alcohol 4 could
be produced in good yield directly from D-glucal, and could serve as an excellent precursor to target
isolevoglucosenone through simple oxidation of the -OH function at C-4, prompted us to explore this
potential approach further to produce isolevoglucosenone from glucose in only three steps (Scheme
1
). The required 2,3,4-tri-O-acetylglucal was produced according to the recently published, one-pot
1
8
methodology of Koreeda et al. in 93% yield. The deprotection of 1,4,5-tri-O-acetyl-D-glucal with
an aqueous methanolic solution of triethylamine produced free D-glucal. The key step of Ferrier
rearrangement of the unprotected D-glucal was performed according to the published procedure of
Oberdorfer in 48% yield. The final oxidation of alkene 6 was performed under various conditions
as reported in the Experimental section. The method of choice was, however, oxidation with manganese
dioxide with a high 82% yield.
1
6
Scheme 1.
The NMR data clearly confirm the identity of the target isolevoglucosenone. Our reported procedure
has significant practical advantages over existing methods and is capable of producing pure (−)-
isolevoglucosenone 2 directly from glucose in multigram quantities cheaply, in only three steps, and in
48% overall yield. Its direct synthesis from glucose was also achieved without separation or purification
of the intermediates: the oxidation was performed with manganese dioxide and 2 was obtained in ∼82%
yield (nonoptimized). The HPLC analysis clearly indicates its purity as a homogeneous product.
As noted at the beginning, our recent results1 on Michael addition of sugar thiols to levoglucosenone
show complete stereoselective additions due to its rigid bicyclic framework and steric shielding of the
,2

5
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Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
upper face of the pyranose ring by the 1,6-anhydro ring. Because this particular stereoselectivity is
19
highly predictable, it was also observed in the Michael addition of organometallics and other carbon
2
0,21
nucleophiles
to levoglucosenone. This important observation prompted us to expand this study to
the exploration of the synthetic utility of isomeric isolevoglucosenone by expecting a similar type of
stereoselectively in introducing a sulfur bridge, between two sugar units at C-(1-2) by Michael addition
of 1-thio-sugars in the formation of thiodisaccharides.
2
2
Thiodisaccharides containing sulfur in the glycosidic linkage have been synthesized previously by
2
3–32
a variety of methods,
including S 2-type reactions involving the action of a thiolate anion and a
N
glycosyl halide, and the displacement of a leaving group by 1-thio-glucopyranose.
3
3
34,35
36
The Michael addition of thiols 5, 6,
and 7 to the enone 2 proceeded smoothly with the
formation of β-(1→2)-3-dideoxy-2-thiodisaccharides 8, 9, and 10 in 63–70% yield. The proton–proton
1
coupling in the H NMR spectra of the conjugate addition products 8–10 confirmed that only the 2-axial
adducts were always obtained as a single addition product (Scheme 2). This stereoselectivity as observed
previously in levoglucosenone conjugate addition1
the alkene face opposite the 1,6-anhydro ring.
9–21
proceeds by the attack of incoming nucleophile at
Scheme 2.
The sterically hindered 1,6-anhydro bridge in isolevoglucosenone is, therefore, assumed to effectively
prevent an attack from the upper side of the molecule which could give an access to the alternative
formation of the 2-equatorial addition product.
1
Indeed, the proton–proton coupling in the H NMR spectrum of the conjugate addition products 8,
9
, and 10 confirmed the D-erythro stereochemistry with coupling constants J =0.5 Hz. This coupling
1,2
indicates that the substituent at C-2 is axial with a quasiequatorial relationship between H-1 and H-3, as
1
seen in compounds 8, 9, and 10. The H NMR spectra of the adducts did not show signals corresponding
to the potential D-threo-isomer, clearly demonstrating that the stereochemistry of the addition of thiols 5,
6
, and 7 to enone 2 is completely controlled by the steric bulk of the 1,6-anhydro bridge. The 13C NMR
spectra of all adducts 8, 9, and 10 showed no alkene signals, and the C-3 signal appeared upfield at ca.
37.0–38.4 ppm, respectively.
Ketones 8, 9, and 10 offer potential in the synthesis of precursors of certain amino sugars as reported
1
,2
by us earlier through conventional oximation and highly stereoselective reduction of the acetamido
function. Accessible in a single-step process from isolevoglucosenone and formed in a completely
stereospecific manner, 8, 9, and 10 are potentially useful for syntheses of 4-amino sugars having three
stereogenic centers in the D-ribo configuration.
®
The reduction of the C-4 keto function of ketones 8, 9, and 10 with L-Selectride , followed by in situ
conventional acetylation, proceeded stereoselectively with the formation of the D-ribo-isomers 11, 12,
and 13 in 79% yield. Only trace amounts of the corresponding D-xylo-isomers 11a, 12a, and 13a were
1
detected by H NMR spectroscopy. Additionally, lack of coupling between H-4 and H-5 and coupling
constants of reduction products 11, 12, and 13, J3a,4=7.2–7.6 Hz and J3e,4=4.82 Hz, indicate the axial

Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
523
disposition of the new substituent at C-4. Unlike levoglucosenone 1, where the ketone reduction was
3
7
predictably controlled by the 1,6-anhydro bridge, the analogous reduction of 8, 9, and 10 was expected
to be dominated by the relative steric contribution of the bulky axial substituent at C-2, as well as the
,6-anhydro bridge. This is in full agreement with earlier observations by Horton and co-workers1
4,15
of
1
high stereoselectivity and yet another classical example of the preferential attack of the reducing agent
from the top face on this bicyclic molecule.
Moreover, the H and 13C NMR spectra of 11, 12, and 13 firmly support their assignments as the D-
ribo-configuration. Particularly, the coupling constants between equatorially disposed H-2 and the axially
disposed H-3, J =4.7 Hz, are of great diagnostic value. On the other hand, the more polar equatorial
1
2
,3
alcohols 11a, 12a, and 13a with the β-xylo-configuration (isolated in only ∼3% yield) displayed a
coupling of J =10.4 Hz, as anticipated for the diaxial disposition of H-3a and H-4 (Scheme 3).
3
a,4
Scheme 3.
The cleavage of the 1,6-anhydro ring in 11, 12, and 13 was examined under various reaction conditions.
Acetolysis using trifluoroacetic acid and acetic anhydride afforded an anomeric mixture of heptaacetates
14 and 15 in good yield (62%). Acetolysis, under similar conditions, such as acetic anhydride and a
catalytic amount of boron trifluoride etherate (BF ·Et O), also gave a good yield (58%). However,
3
2
chromatographic purification of the crude material was required. Compound 13 undergoes almost
total decomposition under the above reaction conditions. The development of alternative deprotection
approaches, particularly for acid sensitive fucose derivatives, is underway.
The method of choice was acetolysis using an acetic anhydride solution and a catalytic amount of
trifluoromethanesulfonate, performed according to the convenient protocol of Fraser-Reid et al.38 This
resulted in the formation of an anomeric mixture of heptaacetates 14 and 15 (α:β, 1:5) in 91% yield.
The presence of the deoxy group at C-3 clearly indicates the strong influence of the 1,6-anhydro ring
on the cleavage, and requires a prolonged reaction, up to the 12 h, as compared with the literature data
3
8
reported. Separation of the anomers proved impossible because of their almost identical R values.
f
1
13
However, the H NMR and C NMR spectra and mass spectral data for the mixture firmly established
their identity.
Final deprotection of heptaacetates 14 and 15 was performed with an aqueous methanolic solution of
triethylamine (4:1:5 MeOH:Et N:H O) at room temperature for 6 h which produced new thiodisaccha-
3
2
rides, 2-S-(β-D-glucopyranosyl)-2-thio-D-3-deoxyglucopyranose 16 and 2-S-(β-D-galactopyranosyl)-2-
thio-D-3-deoxyglucopyranose 17, in 89% yield.
Molecular model of selected 2-S-(β-D-galactopyranosyl)-2-thio-D-3-deoxyglucopyranose 17 (Fig. 2)
clearly confirms the stereogeometry as determined by NMR spectroscopy and the length of the sulfur
bridge between C-1–S is 1.8121 Å, whereas at C-2–S it is 1.8104 Å and the dihedral angle for
C–S–C bridge is 109.8°. All the measurements are similar to the calculation for the sulfur bridge of

5
24
Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
other thiodisaccharides and are substantially different than that of the oxygen counterpart as previously
3
9,40
postulated in the literature.
3. Conclusion
The conjugate addition of protected 1-thiosugars to isolevoglucosenone, followed by the tandem
reaction of C-4 keto group reduction and deprotection, is a new short stereoselective approach to (1→2)-
-S-thiodisaccharides. All functionalized new thiodisaccharides are stable glycomimetic compounds of
potential biological interest.
2
4. Experimental
4.1. General methods
Unless otherwise noted, starting materials were obtained from commercial suppliers and used without
purification. All melting points were uncorrected and were measured in open capillary tubes. Optical
rotations were determined on a Jasco Model DIP-370 polarimeter in CHCl solutions. Thin-layer
3
chromatography (TLC) was performed on precoated silica gel 60F254 plates from E. Merck and visualized
by spraying with 10% ethanolic sulfuric acid and subsequent heating. Column chromatography was
performed on silica gel 60 (70–230 mesh, Merck No. 34).
1
H NMR spectra: NMR samples were prepared in CDCl (99.8 atom% D), filtered, freeze-thawed, and
3
sealed in a 5 mm NMR tube. Tetramethylsilane (TMS) was used as an internal chemical shift reference.
High-resolution NMR spectra were obtained on a Bruker DMX-500 spectrometer. Mass spectra were
obtained either in EI mode at 70 eV or using CI (NH3).
4.2. 1,6-Anhydro-2,3-dideoxy-β-D-erythro-hex-2-enopyranose 4
1
6,17
Compound 4 was produced by Oberdorfer and co-workers’
methodology. R =0.59 (EtOAc), mp
f
1
2
6
0–61.5°C, lit. 58–59°C, [α] +318 (c 1.0, CHCl ), [α] +318 (c 1.0, CHCl ): for NMR data see the
D
3
D
3
8
16,17
13
16
lit.
For C NMR see the lit.
4.3. 1,6-Anhydro-2,3-dideoxy-β-D-glycero-hex-2-enopyranos-4-ulose 2 (isolevoglucosenone)
(a) The crude allylic alcohol 4 (2.56 g, 20 mmol) was dissolved in dichloromethane (30 mL).
Pyridinium dichromate (PDC) (9.63 g, 25.6 mmol) was added to the mixture while stirring at room
temperature for 40 h. Filtration through a column of silica/sand/Celite and concentration afforded a brown
syrup (1.5 g, 59.5%) which was flash chromatographed using 5:1 n-pentane:Et O to produce the enone
2
2
as a pale yellow oil (1.26 g, 50%).
b) The crude allylic alcohol 4 (2.56 g, 20 mmol) was dissolved in chloroform (30 mL) and manganese
(
dioxide (MnO ) (29 g, 334 mmol) was added while stirring at room temperature for 6 h. After filtration,
2
the mixture was evaporated to a syrup and flash chromatographed with 5:1 n-pentane:Et O to give enone
2
2
(2.06 g, 82%) as a pale yellow oil.
1
4,15
(c) One-pot preparation of 2:
to a magnetically stirred suspension of D-glucose monohydrate (10.0
g, 53.7 mmol) in acetic anhydride (36.1 g, 7.0 mmol) 1.0 g of 31% HBr/AcOH was added in portions

Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
525

5
26
Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
while maintaining the mixture at room temperature. After 1 h, the clear solution was treated with an
additional amount (74 g) of 31% HBr/AcOH and the resulting solution was stirred overnight at room
temperature. Anhydrous sodium acetate (30 g) was then added to neutralize the excess of HBr, and the
resulting solution was immediately added in portions to an aqueous suspension of copper sulfate (2.6 g)
and zinc (102 g), in 100 ml of water and acetic acid (150 mL) containing sodium acetate trihydrate (125
g). The mixture was vigorously stirred at room temperature for 2 h. The inorganic solid was filtered off
and washed with ethyl acetate (700 mL) and water (1 L). The inorganic solid must be wet all the time to
deactivate the zinc! The organic layer of the filtrate after separation was washed with a saturated aqueous
solution of NaHCO (1 L) and brine (500 mL), and dried with anhydrous sodium sulfate. The solvent
3
was evaporated on a rotary evaporator to a syrup (14.5 g, 95.4%). Then the colorless syrup was dissolved
in 150 mL of aqueous methanolic solution of triethylamine, 4:5:1 MeOH:H O:Et N, and stirred at room
2
3
temperature until TLC indicated the completion of the reaction (5–8 h). The solution was evaporated to
a syrup (7.39 g), dried overnight in a vacuum over P O , and dissolved in dry tetrahydrofuran (THF)
2
5
(140 mL). Anhydrous copper sulfate (59.4 g, 372 mmol) and 4 Å molecular sieves (5.0 g) were added,
and the mixture was refluxed while vigorously stirred for 6 h. After filtration of the inorganic material
and washing with anhydrous THF (20 mL), the combined filtrate was evaporated to a syrup (3.23 g,
50% yield). The resulting syrup was dissolved in dry chloroform (175 mL) and manganese oxide (35
g, 402 mmol) was added in portions while stirring vigorously for 6 h. The progress of the oxidation
was monitored by TLC. After filtering the inorganic material, the solution was evaporated on a rotary
evaporator to form a brown syrup (2.7 g), which was flash chromatographed by elution with 5:1 n-
pentane:Et O. The fraction of R =0.48 was collected and evaporated to a syrup. The chromatographic
2
f
purification gave enone 2 (2.45 g, 82% yield) as a pale yellow oil. Enone 2 could be obtained as an
analytically pure colorless syrup after a second chromatographic purification using 5:1 n-pentane:Et O
2
11
1
13
(
[α] +319.6 (c 1.0, CHCl ); lit. [α] +321 (c 1.0, CHCl )). The H NMR and C NMR spectra of 2
D
3
D
3
13–15
were identical with those published in the literature.
4.4. General method for the preparation of 3-deoxy-(1→2)-S-thiodisaccharides 8–10
1
3–15
To a solution of isolevoglucosenone
-thio-sugar 5, 6,
2 (126 mg, 0.1 mmol) in acetonitrile (10 mL) a solution of
3
3
34,35
36
1
or 7 (125 mg, 0.34 mmol) in 5 mL of acetonitrile was added dropwise. The
reaction mixture was stirred at room temperature for 24 h. After evaporation of the solvent, the syrupy
residue was purified by column chromatography on silica gel. The fraction eluted with 20% ethyl acetate
in hexane (v/v) gave pure syrupy products, which crystallized from ether–hexane.
4
4
.4.1. 1,6-Anhydro-3-deoxy-2-S-(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl)-D-glycero-hexopyranos-
-ulose 8
30
Yield (436 mg, 89%), mp 157–158.5°C; R =0.59 (1:4 hexane:EtOAc); [α] −124.21 (c 0.84, CHCl );
f
3
+
1
13
HRMS (M) m/z: calcd for C H O S: 490.47. Found: 490.11. The H NMR and C NMR spectra of
2
0
26 12
8
are listed in Tables 1 and 2, respectively.
4
4
.4.2. 1,6-Anhydro-3-deoxy-2-S-(2,3,4,6-tetra-O-acetyl-β-galactopyranosyl)-D-glycero-hexopyranos-
-ulose 9
30
Yield (385 mg, 78.5%), mp 151–152.5°C; R =0.41 (1:4 hexane:EtOAc); [α] −122.2 (c 0.8, CHCl );
f
3
+
1
13
HRMS (M) m/z: calcd for C H O S: 490.47. Found: 490.11. The H NMR and C NMR spectra of
2
0
26 12
9
are listed in Tables 1 and 2, respectively.

Table 1
1
a
H NMR chemical shifts (δ) and coupling constants (J in hertz) for compounds 8–17

5
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Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532

Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
529
4.4.3. 1,6-Anhydro-3-deoxy-2-S-(2,3,4-tri-O-acetyl-L-fucopyranosyl)-D-glycero-hexopyranos-4-ulose
1
0
30
Yield (360 mg, 73.4%), mp 135–138.5°C; R =0.49 (1:4 hexane:EtOAc); [α] −134 (c 0.84, CHCl );
f
3
+
1
13
HRMS (M) m/z: calcd for C H O S: 432.44. Found: 432.27. The H NMR and C NMR spectra of
1
8
24 10
10 are listed in Tables 1 and 2, respectively.
4.5. General method for the reduction of 3-deoxy-(1→2)-S-thiodisaccharides 8–10
To a cooled and stirred solution of thiodisaccharides 8–9 (210 mg, 0.428 mmol) in THF, L-Selectride®
(
3
1 M in THF, 1.0 mL) was added at −78°C under an Ar atmosphere. The reaction mixture was stirred for
h, and then pyridine (4 mL) and acetic anhydride (5 mL) were added and stirred at room temperature
overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract
was washed and dried. Removal of the solvent in vacuo after coevaporation with 1:1 toluene:ethyl alcohol
(
5×30 mL) afforded an oily residue that was subjected to column chromatography on silica gel. The
fraction eluted with 20% ethyl acetate in hexane (v/v) gave syrupy products 11–12.
4.6. 4-O-Acetyl-1,6-anhydro-3-deoxy-2-S-(2,3,4,6-tetra-O-acetyl-2-thio-β-glucopyranosyl)-β-D-ribo-
hexopyranose 11 and 4-O-acetyl-1,6-anhydro-3-deoxy-2-S-(2,3,4,6-tetra-O-acetyl-4-thio-β-gluco-
pyranosyl)-β-D-xylo-hexopyranose 11a
3
0
Yield 11 (190 mg, 79%), R =0.42 (1:4 hexane:EtOAc); [α] −34.2 (c 0.84, CHCl ); and 11a R =0.29
f
3
f
3
0
+
(
5
1:4 hexane:EtOAc) (6 mg, 3%); [α] −12.1 (c 0.84, CHCl ); HRMS (M) m/z: calcd for C H O S:
3
22 30 13
1
13
34.53. Found: 534.14. The H NMR and C NMR spectra of 11 and 11a are listed in Tables 1 and 2,
respectively.
4.7. 4-O-Acetyl-1,6-anhydro-3-deoxy-2-S-(2,3,4,6-tetra-O-acetyl-2-thio-β-galactopyranosyl)-β-D-
ribo-hexopyranose 12 and 4-O-acetyl-1,6-anhydro-3-deoxy-2-S-(2,3,4,6-tetra-O-acetyl-4-thio-β-
galactopyranosyl)-β-D-xylo-hexopyranose 12a
3
0
Yield 12 (170 mg, 81.5%), R =0.38 (1:4 hexane:EtOAc); [α] −30.4 (c 0.68, CHCl ); and 12a
f
3
30
+
R =0.25 (1:4 hexane:EtOAc) (16 mg, 1%); [α] −12.1 (c 0.68, CHCl ); HRMS (M) m/z: calcd for
f
3
1
13
C H O S: 534.53. Found: 534.14. The H NMR and C NMR spectra of 12 and 12a are listed in
2
2
30 13
Tables 1 and 2, respectively.
4.8. 4-O-Acetyl-1,6-anhydro-3-deoxy-2-S-(2,3,4-tri-O-acetyl-2-thio-α-L-fucopyranosyl)-β-D-ribo-
hexopyranose 13 and 4-O-acetyl-1,6-anhydro-3-deoxy-2-S-(2,3,4-tri-O-acetyl-4-thio-α-L-fuco-
pyranosyl)-β-D-xylo-hexopyranose 13a
3
0
From 10 (200 mg, 46 mmol) the yield of 13 (170 mg, 80%), R =0.31 (1:4 hexane:EtOAc); [α]
f
30
−
130.2 (c 0.6, CHCl ); and 13a R =0.28 (1:4 hexane:EtOAc) (8 mg, 4%) [α] −12.1 (c 0.68, CHCl );
3
f
3
+ 1 13
HRMS (M) m/z: calcd for C H O S: 476.50. Found 476.28. The H NMR and C NMR spectra of
2
0
28 11
13 and 13a are listed in Tables 1 and 2, respectively.

5
30
Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
4.9. General methods for the hydrolysis of 3-deoxy-(1→2)-S-thiodisaccharides (11–12)
Thiodisaccharide 11 or 12 (0.2 g, 0.375 mmol) was dissolved in Ac O (8.5 mL) and CF COOH (6.2
2
3
mL), and the mixture was stirred at room temperature for 10 h. After the solvent was evaporated, the
resulting brown syrup was chromatographed (2:1 hexane:Et OAc) to afford an anomeric mixture of
2
heptaacetate 15–16 a as colorless syrup (α:β ratio 1:5) (160 mg, 62%).
Thiodisaccharide 11 or 12 (0.4g, 0.75 mmol) was dissolved in Ac O (8.5 mL). Boron trifluoride
2
etherate (BF ·Et O) (0.1 mL) was added, and the mixture was stirred at room temperature for 10 h.
3
2
After the solvent was evaporated, the resulting brown syrup was chromatographed (2:1 hexane:Et OAc)
2
to afford an anomeric mixture of heptaacetate 14–15 as a colorless syrup (α:β ratio 1:5) (0.30 g, 58%).
To a cooled solution (0°C) of 11 or 12 (0.5 g, 0.93 mmol) in acetic anhydride (10 mL) stirred under
argon, two drops (3 µl) of trimethylsilyl trifluoromethanesulfonate were added. TLC, 1:1 EtOAc:hexane,
indicated the completion of the reaction in 12 h. A solution of saturated sodium bicarbonate was added,
the mixture was stirred for 30 min, and the aqueous mixture was extracted three times (3×20 mL) with
ethyl acetate. The combined extracts were washed with saturated sodium hydrogen carbonate (20 mL)
and brine (20 mL), and dried over sodium sulfate. Evaporation of the solvent under reduced pressure
yielded an inseparable anomeric mixture (α:β in a ratio ca. 1:6).
4
.10. 3-Deoxy-2-S-(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl)-1,2,6-tri-O-acetyl-1-thio-α,β-D-gluco-
pyranose 14
3
0
Yield (0.648 g, 91%) as a colorless syrup, R =0.34 and R =0.31 (1:4 hexane:EtOAc); [α] −12.4 (c
f
f
+
1
13
0
.82, CHCl ); HRMS (M) m/z: calcd for C H O S: 636.62. Found: 636.17. The H NMR and
C
3
26 36 16
NMR spectra of 14 (mainly the β-anomer) are listed in Tables 1 and 2, respectively.
4
.11. 3-Deoxy-2-S-(2,3,4,6-tetra-O-acetyl-β-galactopyranosyl)-1,2,6-tri-O-acetyl-1-thio-α,β-D-gluco-
pyranose 15
3
0
Yield (0.641 g, 86%) as a colorless syrup, R =0.42 and R =0.41 (1:4 hexane-EtOAc); [α] −12.4 (C
f
f
+
1
13
0
.82 CHCI ); HRMS (M) m/z: calcd for C H O S: 636.62. Found: 636.17. The H NMR and
C
3
26 36 16
NMR spectra of 15 (mainly the β-anomer) are listed in Tables 1 and 2, respectively.
4.12. General methods for the deprotection of 3-deoxy-(1→2)-S-thiodisaccharides 14–15
Thiodisaccharides 14–15 (0.250 mg, 0.15 mmol) were dissolved in a 15 ml solution of 4:1:5
MeOH:Et N:H O, and stirred at room temperature. The TLC indicated the completion of the reaction
3
2
after 6 h. Evaporation of the solvent produced an inseparable anomeric mixture (α:β in a ratio 1:6)
4.13. 2-S-(β-D-Glucopyranosyl)-2-thio-D-3-deoxyglucopyranose 16
Yield (119 mg, 89%) as a colorless syrup; [α]30 −10.26→−16.2 (c 0.82, H O); HRMS (M) m/z:
+
2
1
13
calcd for C H O S: 342.36. Found: 342.09. The H NMR and C NMR spectra of 16 are listed in
1
2
22
9
Tables 1 and 2, respectively.

Z. J. Witczak et al. / Tetrahedron: Asymmetry 11 (2000) 519–532
531
4.14. 2-S-(β-D-Galactopyranosyl)-2-thio-D-3-deoxyglucopyranose 17
Yield (88 mg, 66%) as a colorless syrup; [α]30 −12.26→−14 (c 0.8, H O); HRMS (M) m/z: calcd
+
2
1
13
for C H O S: 342.36. Found: 342.12. The H NMR and C NMR spectra of 17 are listed in Tables 1
1
2
22
9
and 2, respectively.
Acknowledgements
Financial support from the American Cancer Society Institutional Grant to University of Connecticut
Health Center, ACSIN 152L-132 grant program, is gratefully acknowledged.
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