Synthesis of the 3-methyl ether and 4-deoxy derivatives of 4-cyanophenyl 1,5-dithio-β-D-xylopyranoside (Beciparcil)

Article abstract of DOI:10.1016/S0008-6215(99)00045-2

Treatment of the 2,3-isopropylidene acetal of the title dithioxyloside with 2,4,5-triiodoimidazole-PPh₃ caused replacement of the 4-hydroxyl group by iodine to afford 82% of the 4-axial iodide 6, converted by base into 4-cyanophenyl 2,3-O-isopropylidene-1,5-dithio-β-D-glycero-pent-3-enopyranoside (8). Acid treatment of 8 gave 87% of the deacetonated glycos-3-ulose, borohydride reduction of which afforded 63% of 4-cyanophenyl 4-deoxy-1,5-dithio-α-L-threo-pentopyranoside (3), together with 27% of the 3-axial epimer. The 3-methyl ether of the title dithioxyloside was satisfactorily prepared via 2,4-protection as the cyclic phenylboronate, methylation, and deprotection; alternative strategy via the 2,4-bis(triisopropylsilyl) ether was complicated because of silyl-group migration under methylation conditions. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00045-2

Carbohydrate Research 316 (1999) 104–111
Synthesis of the 3-methyl ether and 4-deoxy derivatives
of 4-cyanophenyl 1,5-dithio-b-
D-xylopyranoside
(Beciparcil)ꢀ
Yun Li a, Derek Horton a,*, Ve´ronique Barberousse b, Soth Samreth b,
Franc¸ois Bellamy b
a Department of Chemistry, The Ohio State Uni6ersity, Columbus, OH 43210, USA
b Laboratoires Fournier S.A., Centre de Recherche, 50 rue de Dijon, F-21121 Daix, France
Received 16 December 1998; accepted 8 February 1999
Abstract
Treatment of the 2,3-isopropylidene acetal of the title dithioxyloside with 2,4,5-triiodoimidazole–PPh3 caused
replacement of the 4-hydroxyl group by iodine to afford 82% of the 4-axial iodide 6, converted by base into
4-cyanophenyl 2,3-O-isopropylidene-1,5-dithio-b-
of the deacetonated glycos-3-ulose, borohydride reduction of which afforded 63% of 4-cyanophenyl 4-deoxy-1,5-
dithio-a- -threo-pentopyranoside (3), together with 27% of the 3-axial epimer. The 3-methyl ether of the title
D
-glycero-pent-3-enopyranoside (8). Acid treatment of 8 gave 87%
L
dithioxyloside was satisfactorily prepared via 2,4-protection as the cyclic phenylboronate, methylation, and deprotec-
tion; alternative strategy via the 2,4-bis(triisopropylsilyl) ether was complicated because of silyl-group migration
under methylation conditions. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Xylosides; Dithio sugars; 1,5-Dithioxylosides; Antithrombotic agents
1. Introduction
biological evaluation in vivo and as substrates
for glycosyltransferases involved in gly-
cosaminoglycan biosynthesis. Previous papers
have recorded conversion of this dithioxyl-
oside into the 2- and 4-methyl ethers and
4-deoxy-4-fluoro derivatives [2] and inversion
transformations at the 4-position [1]. This re-
port presents synthesis of the 3-methyl ether 2
and 4-deoxygenated products 3 and 4 from
the parent dithioxyloside 1.
A quest for orally active antithrombotic
agents based on structural modifications of
the lead compound 4-cyanophenyl 1,5-dithio-
b- -xylopyranoside (Beciparcil, 1) has prom-
D
pted the synthesis of a series of analogues for
ꢀ Part III of the series ‘Chemistry of 4-cyanophenyl 1,5-
dithio-b-D-xylopyranoside (Beciparcil)’. For Part II, see Ref.
[1].
* Corresponding author. Present address: Department of
Chemistry, American University, 4400 Massachusetts Ave.,
NW, Washington, DC 20016, USA. Tel.: +1-202-885-1767;
fax: +1-202-885-1095.
E-mail address: carbchm@american.edu (D. Horton)
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00045-2

Y. Li et al. / Carbohydrate Research 316 (1999) 104–111
105
Scheme 1.
Scheme 2.
2. Results and discussion
It was found that even such excellent nucle-
ophiles as thiolacetate (1.5 equiv) or azide (1.6
equiv) in N,N-dimethylformamide (DMF) so-
lution at room temperature failed to effect
Synthesis of 4-deoxy deri6ati6es.—The con-
veniently accessible [2] 4-cyanophenyl 2,3-O-
isopropylidene-1,5-dithio-b-
D-xylopyranoside
SN
2 displacement of iodide from 6; instead
these reagents acted as bases to abstract H-3
and effect 2 trans-diaxial elimination to give
(5) was a logical precursor for the target 4-de-
oxygenated analogue 3 of the title dithioxyl-
oside, but the presence of the 4-cyano-
phenylthio group in the molecule, an effective
radical trap, made an established method for
deoxygenation, via tributylstannane treatment
of a derived 4-xanthate [3], inapplicable in this
instance. An alternative approach, based on the
introduction of iodide at the 4-position, was
explored. Two procedures were examined for
replacement of the 4-hydroxyl group by iodide,
based on the reaction of 5 with 2,4,5-triiodoim-
idazole–PPh3 or with imidazole–I2–PPh3 [4,5].
Both procedures effected the desired reaction,
but the former gave the higher (87%) net yield
as well as higher stereoselectivity, with 82% of
the axial 4-iodo derivative 6 and only 5% of the
equatorial 4-iodo derivative 7 (Scheme 1).
E
the enol–ether derivative 8, obtained in 85%
yield when azide was the reagent. In neither
instance was the alternative 4,5-trans-elimina-
tion product observed, although when sodium
acetate (4 equiv) was used the 80% of elimina-
tion product formed was found by NMR
spectroscopy to be a 3:1 mixture of the 3,4-
elimination product 8 and the 4,5-elimination
product 9. The latter compound had been
obtained earlier [1] from 5 by the Mitsunobu
reaction. This convenient access to 4-
cyanophenyl 4-deoxy-2,3-O-isopropylidene-b-
D-glycero-pent-3-enopyranoside (8) provided
a suitable route not involving radical chem-
istry to the desired 4-deoxygenated structure
(Scheme 2).

106
Y. Li et al. / Carbohydrate Research 316 (1999) 104–111
Scheme 3.
Scheme 4.
Mild acid treatment of compound 8 effected
vored. Accordingly, the triol 1 was treated
with chlorotriisopropylsilane (TIPSCl)–
pyridine in anhydrous DMF, under promo-
tion by silver nitrate [7], and the 2,4-disilylated
product 11 was obtained as a colorless crys-
talline solid in 36% yield.
hydrolysis of the enol ether and removal of
the isopropylidene group to give the crys-
talline glycos-3-ulose derivative 10 in 87%
yield. Reduction of 10 with sodium borohy-
dride afforded the 3-equatorial alcohol 3 as
the major compound (63% yield) and its 3-ax-
ial epimer 4 as the minor product (27% yield).
It was envisaged that methylation of 11
followed by desilylation would provide a
straightforward route to the desired 3-methyl
ether. However, attempts to methylate 11 led
to migration of the TIPS group under the
alkaline conditions of the methylation
(Scheme 4).
Compound 11 was first methylated with
sodium hydride–iodomethane in anhydrous
DMF, and the crude product was then desily-
lated (Bu4NF·3H2O in THF). At this stage,
TLC (4:1 EtOAc–hexane) showed only one
single spot, but the 1H NMR spectrum
showed a mixture of two products. In order to
assign the structures, the mixture was fully
acetylated [acetic anhydride–pyridine–4-
1
The structural assignments were based on H
NMR spectra; compound 3 showed J2,3=8.1
Hz, whereas 4 showed J2,3 =2.6 Hz, indicating
that H-3 in 3 is axially disposed, and H-3 in 4
is equatorial (Scheme 3).
Synthesis of 4-cyanophenyl 3-O-methyl-1,5-
dithio-i- -xylopyranoside (2).—In order to
D
prepare the target 3-methyl ether 2 from the
starting triol 1, a suitable strategy for protect-
ing the 2- and 4-hydroxyl groups was re-
quired. It was expected that the bulky
triisopropylsilyl (TIPS) group would provide
good selectivity at the C-2 and C-4 positions
because the C-3 position is sterically unfa-

Y. Li et al. / Carbohydrate Research 316 (1999) 104–111
107
Scheme 5.
dimethylaminopyridine (cat.) in CH2Cl2].
Purification by chromatography over silica gel
(3:2 Et2O–hexane) afforded the 2,4-diacetate
12 of the desired 3-methyl ether, but in only
low yield (11%), together with the diacetylated
2-methyl ether 13 as the major product (58%
yield).
lowed by saponification of the protecting
group with Amberlite IRA-400 (HO−) resin.
The crystalline product isolated was the de-
sired 3-methyl ether 2, obtained in a net yield
of 30% from 1 (Scheme 5).
Methylation of 11 by using silver oxide–
iodomethane in anhydrous DMF afforded a
mixture of three compounds 12, 13, and the
4-methyl analogue 14 in the ratio of 2:5:3 (as
3. Experimental
General methods.—TLC was performed on
precoated plates of Silica Gel 60F-254 (E.
Merck); components were detected by UV
light and by spraying the plates with 10%
H2SO4 and subsequent heating. Melting points
were determined with a Thomas–Hoover ap-
paratus and are uncorrected. Specific rotations
were recorded with a Perkin–Elmer 141 polar-
imeter. 1H and 13C NMR spectra were
recorded with Bruker AM 250 or AM 300
spectrometers, and chemical shifts refer to an
internal standard of Me4Si (l=0.00). Mass
spectra were recorded at The Ohio State Uni-
versity Chemical Instrument Center with
Kratos MS-30 and VG 70-250S mass spec-
trometers operating in the electron-impact or
chemical-ionization mode as indicated. Ele-
mental analyses were performed by Atlantic
Microlabs, Atlanta, GA.
1
determined by H NMR data). An authentic
sample of compound 14 was prepared by
acetylating the known 4-cyanophenyl 4-O-
methyl-1,5-dithio-b- -xylopyranoside [2].
D
These results showed that the TIPS group
was less than satisfactory for the intended
purpose. Evidently an initially produced 3-
oxyanion displaces the protecting group at
O-2 and the resultant 2-oxyanion directs
etherification at this position as the major
reaction outcome. Attempts to utilize the ben-
zoyl group for 2,4-protection were even less
satisfactory; subsequent methylation under the
aforementioned conditions led to almost ex-
clusive 2-methylation.
An effective preparative route to the target
3-methyl ether 2 was accomplished by using
phenylboronic anhydride [(PhBO)3] [6] as a
reagent to introduce into compound 1 the
2,4-cyclic phenylboronate protecting group,
which affords the requisite alkali stability for
the conditions of methylation. Thus the
dithioxyloside 1 was treated with 0.35 equiv of
(PhBO)3 in toluene in the presence of crushed
Iodination of 4-cyanophenyl 2,3-O-isopropyl-
idene-1,5-dithio-i- -xylopyranoside (5).—To
D
a solution of 5 [2] (345 mg, 1.07 mmol) in
anhydrous toluene (22 mL) was added PPh3
(1.12 g, 4 equiv) and 2,4,5-triiodoimidazole [5]
(0.953 g, 2 equiv). The mixture was heated
under argon at 120 °C (bath) for 1.5 h. After
cooling to room temperature (rt), saturated aq
NaHCO3 (3 mL) was added. Iodine was then
added to the mixture until the organic layer
,
4 A molecular sieve, and the crude product
obtained was directly methylated with silver
oxide–iodomethane in anhydrous DMF, fol-

108
Y. Li et al. / Carbohydrate Research 316 (1999) 104–111
HRMS Calcd for C15H16INO2S2: 432.967.
Found: 432.964.
remained red–brown in color for 10 min.
After extraction with ether (3×50 mL), the
ether layer was washed with 5% aq Na2S2O3
(to remove the excess of I2), and then water
(15 mL), dried (MgSO4), and evaporated.
The crude product was purified by chro-
matography on silica gel (1:4 to 2:3 Et2O–
hexane) to afford first the equatorial 4-iodo
product 7 (23 mg, 5%) as a colorless solid,
and later the axial 4-iodo product 6 as a
colorless solid (378 mg, 82%).
Treatment of 5 (217 mg, 0.67 mmol) by the
same procedure with PPh3 (2.5 equiv), imida-
zole (2.2 equiv), and iodine (1.1 equiv) in
toluene (5 mL) for 35 min afforded, after
column chromatography on silica gel, the 4-
axial product 6 (151 mg, 52%) and the 4-
equatorial product 7 (44 mg, 15%).
4-Cyanophenyl
2,3-O-isopropylidene-1,5-
dithio-i- -glycero-pent-3-enopyranoside (8).
D
—To a solution of the 4-axial iodide 6 (877
mg, 2.03 mmol) in anhydrous DMF (20 mL)
was added NaN3 (216 mg, 1.6 equiv). After
48 h at rt, Et2O (250 mL) was added. The
organic solution was washed with water (5×
10 mL), dried (MgSO4), and evaporated to
afford 8 as a pure (NMR), colorless solid
(500 mg, 80%) that was used directly for the
next step (a decrease in yield resulted if the
crude product was purified by chromatogra-
phy on silica gel with 1:4 Et2O–hexane as
eluent), mp (from EtOH) 64.5–65 °C, [h]D19
+84.0° (c 0.47, CHCl3); 1H NMR (250
MHz, CDCl3): l 7.61 (m, 4 H, Ar), 4.96 (dt,
1 H, J2,4 1.9, J4,5a=J4,5b =3.7 Hz, H-4), 4.59
(dddd, 1 H, J1,2 9.6, J2,5a 2.6 Hz, J2,5b 2.1 Hz,
H-2), 4.21 (d, 1 H, H-1), 3.57 (ddd, 1 H,
J5a,5b 16.0 Hz, H-5a), 3.09 (ddd, 1 H, H-5b),
1.51 (s, 3 H, Me), 1.49 (s, 3 H, Me); 13C
NMR (75 MHz, CDCl3): l 150.8 (C-3), 140.1
(Ar-C), 132.2 (Ar-CH), 130.4 (Ar-CH), 118.3
(Ar-C), 110.5 (Me2CO2), 110.2 (CN), 89.9
(C-4), 74.6 (C-2), 49.1 (C-1), 26.8 (C-5), 26.6
(Me), 24.8 (Me); MS (EI): 305 (0.3, M+),
171 (7.0, M−SC6H4CN), 135 (12.7,
HSC6H4CN), 126 (15.6, M−SC6H4CN−
SCH2 +1), 113 (13.8, M−SC6H4CN−
Me2CO), 55 (100).
4-Cyanophenyl 4-deoxy-4-iodo-2,3-O-iso-
propylidene-1,5-dithio-h- -arabinopyranoside
L
(6) had mp (from EtOH) 153–155 °C (dec),
1
[h]2D0 +121.5° (c 0.67, CHCl3), H NMR (250
MHz, CDCl3): l 7.63 (m, 4 H, Ar), 4.87 (m,
1 H, H-4), 4.45 (d, 1 H, J1,2 10.4 Hz, H-1),
4.03 (dd, 1 H, J2,3 8.4 Hz, H-2), 3.40 (dd, 1
H, J4,5a 2.9, J5a,5b 15.2 Hz, H-5a), 2.82 (dd, 1
H, J4,5b 3.0 Hz, H-5b), 2.52 (dd, 1 H, J3,4 3.2
Hz, H-3), 1.49 (s, 3 H, Me), 1.48 (s, 3 H,
Me); 13C NMR (63 MHz, CDCl3): l 139.3
(Ar-C), 132.3 (Ar-CH), 131.4 (Ar-CH), 118.4
(Ar-C), 111.1 (Me2CO2), 109.4 (CN), 79.8
(C-3), 77.3 (C-2), 51.4 (C-1), 39.2 (C-5), 29.6
(C-4), 27.0 (Me), 26.9 (Me); MS (EI): 433
(2.9, M+), 299 (19.8, M−SC6H4CN), 241
(62.2, M−SC6H4CN−Me2CO), 171 (36.3,
M−SC6H4CN−HI), 128 (9.1, HI), 116
(100). Anal. Calcd for C15H16INO2S2
(433.31): C, 41.58; H, 3.72. Found: C, 41.60;
H, 3.67.
4-Cyanophenyl 4-deoxy-4-iodo-2,3-O-iso-
propylidene-1,5-dithio-i- -xylopyranoside (7)
D
had mp (from EtOH) 163–164 °C, [h]D25
−106.3° (c 0.80, CHCl3); 1H NMR (250
MHz, CDCl3): l 7.61 (m, 4 H, Ar), 4.42 (d, 1
H, J1,2 10.3 Hz, H-1), 4.18 (ddd, 1 H, J3,4
10.7, J4,5a 11.7, J4,5b 4.2 Hz, H-4), 3.64 (dd, 1
H, J2,3 8.3 Hz, H-2), 3.47 (dd, 1 H, H-3),
3.33 (dd, 1 H, J5a,5b 13.8 Hz, H-5a), 3.08 (dd,
1 H, H-5b), 1.50 (s, 3 H, Me), 1.48 (s, 3 H,
Me); 13C NMR (63 MHz, CDCl3): l 138.8
(Ar-C), 132.3 (Ar-CH), 131.6 (Ar-CH), 118.2
(Ar-C), 111.2 (Me2CO2), 108.1 (CN), 84.4,
79.1 (C-2, 3), 51.2 (C-1), 38.7 (C-5), 26.7
(Me), 26.5 (Me), 21.7 (C-4); MS (EI): 433
(1.2, M+), 299 (3.0, M−SC6H4CN), 241
(65.3, M−SC6H4CN−Me2CO), 114 (19.4,
M−SC6H4CN−Me2CO−I), 113 (21.2,
M−SC6H4CN−Me2CO−HI), 65 (100).
This product was unstable and decom-
posed before an elemental analysis could be
obtained.
When compound 6 (100 mg, 0.23 mmol)
was treated by the same procedure with
NaOAc·3H2O (4 equiv) in DMF (3 mL) for
48 h, a chromatographically homogeneous
pro-duct (56 mg, 80%) was isolated, but its
NMR spectrum showed it to be a 3:1 mixture
of 8 and an isomeric product determined to
be 4-cyanophenyl 2,3-O-isopropylidene-1,5-
dithio-a-
L
-threo-pent-4-enopyranoside
(9).
Compound 9 has already been reported [1].

Y. Li et al. / Carbohydrate Research 316 (1999) 104–111
109
4-Cyanophenyl 1,5-dithio-i-
D
-glycero-pen-
total yield of 63%, mp (from EtOAc–hexane)
141–141.5 °C, [h]D19 +23.3° (c 0.46, MeOH);
1H NMR (250 MHz, Me2SO-d6/D2O): l 7.74
(m, 2 H, Ar), 7.60 (m, 2 H, Ar), 4.43 (d, 1 H,
J1,2 9.0 Hz, H-1), 3.37 (ddd, 1 H, J2,3 8.1, J3,4a
10.4, J3,4e 3.7 Hz, H-3), 3.31 (dd, 1 H, H-2),
2.78 (ddd, 1 H, J4e,5a 2.5, J4a,5a 11.8, J5a,5e 14.1
Hz, H-5a), 2.51 (m, 1 H, H-5e), 2.20 (m, 1 H,
H-4e), 1.68 (m, 1 H, H-4a); 13C NMR (75
MHz, CDCl3): l 140.1 (Ar-C), 132.5 (Ar-CH),
130.9 (Ar-CH), 118.3 (Ar-C), 111.1 (CN),
76.8, 74.1 (C-2, 3), 53.9 (C-1), 34.7 (C-5), 28.2
(C-4); MS (EI): 249 (0.1, M−H2O), 135 (100,
HSC6H4CN), 133 (4.0, M−SC6H4CN), 115
(19.2, M−SC6H4CN−H2O). Anal. Calcd for
C12H13NO2S2 (267.35): C, 53.90; H, 4.90; N,
5.26. Found: C, 53.73; H, 4.88; N, 5.14.
topyranosid-3-ulose (10).—To a mixture of 8
(77 mg, 0.25 mmol) in MeOH (4 mL) and
H2O (1 mL) was added Amberlite IR-120
(H+) resin (ꢀ15 mg). After 19 h at rt1, the
mixture was heated for 16 h at 50 °C (bath).
After removal of resin over Celite, the solvents
were removed by evaporation under dimin-
ished pressure. The crude product crystallized
from EtOAc–hexane to give 10 as colorless
crystals (43 mg, 64%). The mother liquor was
purified by chromatography on silica gel (2:3
EtOAc–hexane) to furnish an additional 15
mg (22%) of 10 (total yield: 87%), mp (from
EtOAc–hexane) 148 °C, [h]1D9 +21.0° (c 0.21,
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.61
(m, 4 H, Ar), 4.21 (m, 2 H, H-2, OH, D2O
exchangeable), 4.16 (d, 1 H, J1,2 10.5, H-1),
3.02–2.80 (m, 4 H, H-4,5); 13C NMR (75
MHz, CDCl3): l 205.8 (C-3), 139.1 (Ar-C),
132.2 (Ar-CH), 131.9 (Ar-CH), 118.2 (Ar-C),
111.2 (CN), 78.1 (C-2), 56.5 (C-1), 42.3 (C-4),
29.3 (C-5); MS (EI): 265 (1.6, M+), 135 (100,
HSC6H4CN), 131 (25.5, M−SC6H4CN), 113
(2.7, M−SC6H4CN−H2O). Anal. Calcd for
C12H11NO2S2 (265.34): C, 54.32; H, 4.18.
Found: C, 54.14; H, 4.21.
4-Cyanophenyl 4-deoxy-1,5-dithio-i- -ery-
D
thro-pentopyranoside (4), 27% had mp (from
EtOAc–hexane) 97–98 °C, [h]1D8 −159.7° (c
1
0.58, CHCl3); H NMR (250 MHz, CDCl3): l
7.59 (m, 4 H, Ar), 4.52 (d, 1 H, J1,2 8.4 Hz,
H-1), 4.12 (m, 1 H, H-3), 3.80 (ddd, 1 H, J2,OH
5.0, J2,3 2.6 Hz, H-2), 3.03 (ddd, 1 H, J4e,5a 2.7,
J4a,5a 10.1, J5a,5e 13.8 Hz, H-5a), 2.95 (d, 1 H,
OH-2, D2O exchangeable), 2.51 (ddd, 1 H,
J4e,5e 6.0, J4a,5e 3.7 Hz, H-5e), 2.32 (d, 1 H,
J3,OH 4.0 Hz, OH-3, D2O exchangeable), 2.18
(m, 1 H, H-4e), 2.04 (m, 1 H, H-4a); 13C
NMR (63 MHz, CDCl3): l 140.2 (Ar-C),
132.5 (Ar-CH), 131.1 (Ar-CH), 118.3 (Ar-C),
110.8 (CN), 71.9, 68.0 (C-2, 3), 51.7 (C-1),
32.6 (C-5), 24.6 (C-4); MS (EI): 267 (0.1,
M+), 135 (72.0, HSC6H4CN), 133 (12.8, M−
SC6H4CN), 115 (39.8, M−SC6H4CN−H2O),
97 (4.5, M−SC6H4CN−2×H2O). Anal.
Calcd for C12H13NO2S2 (267.35): C, 53.90; H,
4.90; N, 5.26. Found: C, 53.58; H, 4.85; N,
5.16.
Reduction of 4-cyanophenyl 1,5-dithio-i- -
D
glycero-3-pentopyranosid-3-ulose (10).—To a
suspension of compound 10 (422 mg, 1.59
mmol) in MeOH (6 mL) cooled to 0 °C was
added NaBH4 (61 mg, 1 equiv) during 10 min.
After 30 min at 0 °C, 25% aq AcOH (1 mL)
was added and the solvents were evaporated
off under diminished pressure. Water (20 mL)
was added and the mixture extracted with
EtOAc (3×70 mL). The organic layer was
washed with satd aq NaHCO3 (2×20 mL),
and then satd aq NaCl (2×20 mL), dried
(MgSO4), and evaporated. The crude solid
was carefully crystallized from EtOAc–hexane
to furnish 65 mg (15%) of 3 as colorless
crystals. The mother liquor was purified by
chromatography over silica gel (1:1 EtOAc–
hexane) to afford the solid epimer 4 (114 mg,
27%) and 3 (203 mg, 48%).
4-Cyanophenyl 2,4-di-O-(triisopropyl)silyl-
1,5-dithio-i- -xylopyranoside (11).—To a so-
D
lution of the triol 1 (1 g, 3.53 mmol),
chlorotriisopropylsilane (TIPSCl) (3.03 mL, 4
equiv) and pyridine (2.86 mL, 10 equiv) in
anhydrous DMF (10 mL) was added 2.025 g
(3.4 equiv) of AgNO3 under argon. The mix-
ture was stirred under argon for 20 h at rt and
then MeOH (2 mL) was added. After 5 min,
CH2Cl2 (50 mL) was then added and the
mixture was filtered through Celite. The sol-
vent was evaporated off under diminished
4-Cyanophenyl
4-deoxy-1,5-dithio-h- -
L
threo-pentopyranoside (3) was obtained in a
1 It is important to leave the reaction at room temperature
at first. The starting material may be totally decomposed if
heating is initiated directly.

110
Y. Li et al. / Carbohydrate Research 316 (1999) 104–111
(5 mL) was added, and the mixture was ex-
tracted with CH2Cl2 (3×15 mL), dried
(MgSO4), and evaporated to dryness. Purifica-
tion by chromatography over silica gel (3:2
Et2O–hexane) gave the desired 2,4-diacetate
12 (7 mg, 11% from 11) and the 3,4-diacetate
13 (37 mg, 58% from 11).
Method B. To a solution of the 2,4-disilyl-
ated derivative 11 (100 mg, 0.17 mmol) and
MeI (104 mL, 10 equiv) in anhydrous DMF (1
mL) cooled to 0 °C was added under argon
195 mg (5 equiv) of Ag2O in small portions
during 1 h. After stirring for 20 h at rt, EtOAc
(20 mL) was added, and the mixture was
filtered through Celite. The solvent was evapo-
rated off under diminished pressure, and the
crude product was used for the next step
without purification.
pressure and the crude product purified by
chromatography over silica gel (1:9 Et2O–hex-
ane) to afford 11 as a colorless solid (756 mg,
36%), mp (from hexane) 144–144.5 °C, [h]D20
1
+13° (c 0.45, CHCl3); H NMR (250 MHz,
CDCl3): l 7.54 (m, 4 H, Ar), 4.09 (d, 1 H, J1,2
9.9 Hz, H-1), 3.92 (m, 1 H, H-4), 3.88 (dd, 1
H, J2,3 8.4 Hz, H-2), 3.25 (dt, 1 H, J3,OH 1.6,
J3,4 8.4 Hz, H-3), 2.67 (dd, 1 H, J4,5a 10.6,
J5a,5b 13.3 Hz, H-5a), 2.65 (d, 1 H, OH, D2O
exchangeable), 2.57 (dd, 1 H, J4,5b 4.5 Hz,
H-5b), 1.34–1.23 (m, 6 H, 3×CHSi), 1.12–
13
1.06 (m, 36 H, 12×Me); C NMR (63 MHz,
CDCl3): l 142.4 (Ar-C), 132.2 (Ar-CH), 129.2
(Ar-CH), 118.6 (Ar-C), 109.7 (CN), 80.9 (C-
3), 77.0 (C-2), 75.0 (C-4), 54.0 (C-1), 34.4
(C-5), 18.4 (Me), 18.0 (Me), 13.3 (CHSi), 12.5
(CHSi); MS (EI): 534 (0.5, M−i-Pr−H2O),
417 (12.1, M−i-Pr−HSC6H4CN), 378 [3.9,
M−i-Pr−HOSi(i-Pr)3], 59 (100). Anal. Calcd
for C30H53NO3S2Si2 (596.03): C, 60.45; H,
8.96. Found: C, 60.55; H, 9.02.
The desilylation and diacetylation steps
were effected in the same way as in Method A.
The crude product after acetylation was evalu-
1
ated by comparison of its H NMR spectrum
with those of the known 2,4-diacetate 12, 3,4-
diacetate 13, and 2,3-diacetate 14. Compound
14 was prepared from the known 4-
Methylation of 4-cyanophenyl 2,4-di-O-(tri-
sisopropyl)silyl-1,5-dithio-i-
D
-xylopyranoside
(11)
cyanophenyl
4-O-methyl-1,5-dithio-b- -xy-
D
Method A. To a solution of the 2,4-disilyl-
ated product 11 (100 mg, 0.17 mmol) and MeI
(52 mL, 5 equiv) in anhydrous DMF (1 mL)
under argon and cooled to −15 °C was added
13 mg of NaH (80% in mineral oil, 2.5 equiv).
After 30 min at −15 °C, satd aq NH4Cl (5
mL) and Et2O (50 mL) were added. The ether
layer was washed with H2O (3×10 mL), 5%
aq Na2S2O3 (5 mL), H2O (10 mL), and dried
(MgSO4). The solvent was evaporated off un-
der diminished pressure, and the crude
product was used for the next step without
purification.
lopyranoside [2] by the foregoing diacetylation
procedure. In this case, the proportions
(NMR) of 12, 13, and 14 were 2:5:3.
4-Cyanophenyl 2,4-di-O-acetyl-3-O-methyl-
1,5-dithio-i- -xylopyranoside (12): mp (from
D
EtOH) 147.5–148.5 °C, [h]2D1 +11.3° (c 0.88,
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.56
(m, 4 H, Ar), 5.14 (dd, 1 H, J1,2 10.4, J2,3 9.0
Hz, H-2), 4.99 (ddd, 1 H, J4,5a 4.5, J4,5b 10.7,
J3,4 9.3 Hz, H-4), 4.10 (d, 1 H, H-1), 3.47 (s, 3
H, OMe), 3.24 (dd, 1 H, H-3), 2.84 (dd, 1 H,
J5a,5b 13.5 Hz, H-5a), 2.63 (dd, 1 H, H-5b),
2.11 (s, 3 H, CH3CO), 2.08 (s, 3 H, CH3CO);
13C NMR (75 MHz, CDCl3): l 169.6
(CH3CO), 169.3 (CH3CO), 139.9 (Ar-C),
132.3 (Ar-CH), 130.8 (Ar-CH), 118.2 (Ar-C),
110.9 (CN), 83.6, 74.3, 73.5 (C-2, 3, 4), 60.5
(OMe), 50.8 (C-1), 31.1 (C-5), 20.8 (CH3CO),
20.7 (CH3CO); MS (EI): 381 (0.1, M+), 215
(12.1, M−SC6H4CN−MeOH), 155 (9.8,
M−SC6H4CN−MeOH−AcOH), 145 (14.4,
M−SC6H4CN−AcO−Ac), 113 (60.4, M−
SC6H4CN−AcO−Ac−MeOH), 43 (100,
Ac). HRMS Calcd for C17H19NO5S2:
381.0705. Found: 381.0731.
The crude product was dissolved in THF (4
mL) and Bu4NF·3H2O (160 mg, 3 equiv) was
added. After 20 min at rt, EtOAc (50 mL) was
added. The organic layer was washed with
H2O (2×8 mL), dried (MgSO4), and evapo-
rated under diminished pressure. At this stage,
the TLC (4:1 EtOAc–hexane) showed one
single spot, but the 1H NMR spectrum
showed two products.
To a solution of the crude product in
CH2Cl2 (2 mL) was added pyridine (110 mL, 8
equiv), Ac2O (80 mL, 5 equiv), and 4-dimethyl-
aminopyridine (cat.). After 16 h at rt, water

Y. Li et al. / Carbohydrate Research 316 (1999) 104–111
111
To the crude product was added anhydrous
DMF (8 mL) and MeI (1.1 mL, 6 equiv). Ag2O
(2.7 g, 4 equiv) was then added in small portions
during 2 h. After stirring for 20 h at rt, EtOAc
(20 mL) was added and the mixture was filtered
through Celite. The solvent was evaporated off
under diminished pressure, and the crude
product was used for the next step without
purification. To a solution of the crude product
in MeOH (25 mL) was added 3 g of Amberlite
IRA-400 (HO−) resin. After vigorous stirring
for 20 h at rt, MeOH was evaporated off, and
the crude solid was applied to a column of
neutral alumina (activity I) using 1:4 MeOH–
EtOAc as eluant. The product obtained was
then purified over silica gel (EtOAc) to afford
the 3-methyl ether 2 as a colorless solid (257 mg,
30% from 1), mp (EtOAc–hexane) 156–157 °C,
4-Cyanophenyl 3,4-di-O-acetyl-2-O-methyl-
1,5-dithio-i- -xylopyranoside (13): mp (from
D
Et2O) 144.5–145 °C, [h]1D8 +64° (c 0.58,
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.59
(m, 4 H, Ar), 5.04 (m, 2 H, H-2, 4), 4.14 (d, 1
H, J1,2 10.2, H-1), 3.57 (s, 3 H, OMe), 3.45
(dd, 1 H, J2,3 8.9 Hz, H-2), 2.81–2.66 (m, 2 H,
H-5), 2.11 (s, 3 H, CH3CO), 2.02 (s, 3 H,
CH3CO); 13C NMR (63 MHz, CDCl3): l
169.8 (CH3CO), 169.5 (CH3CO), 140.8 (Ar-
C), 132.4 (Ar-CH), 130.3 (Ar-CH), 118.2 (Ar-
C), 110.7 (CN), 84.4, 75.5, 72.2 (C-2, 3, 4),
61.4 (OMe), 52.0 (C-1), 31.3 (C-5), 20.7
(CH3CO); MS (EI): 381 (0.1, M+), 187 (3.5,
M−SC6H4CN−AcOH), 127 (59.3, M−
SC6H4CN−2AcOH),
113
(15.7,
M−
SC6H4CN−AcO−Ac−MeOH), 43 (100,
Ac). Anal. Calcd for C17H19NO5S2 (381.45):
C, 53.52; H, 5.02. Found: C, 53.44; H, 5.03.
4-Cyanophenyl 2,3-di-O-acetyl-4-O-methyl-
[h]2D1 −75° (c 0.23, CHCl3); H NMR (300
1
MHz, CDCl3): l 7.60 (m, 4 H, Ar), 4.05 (d, 1
H, J1,2 9.5 Hz, H-1), 3.83 (m, 1 H, H-4), 3.70
(ddd, 1 H, J2,3 8.4, J2,OH 3.0 Hz, H-2), 3.677 (s,
3 H, OMe), 3.11 (d, 1 H, OH-2, D2O exchange-
able), 2.97 (t, 1 H, J3,4 8.4 Hz, H-3), 2.80 (dd,
1 H, J4,5a 4.3, J5a,5b 13.5 Hz, H-5a), 2.68 (d, 1
H, J4,OH 3.3 Hz, OH-4, D2O exchangeable), 2.68
(dd, 1 H, J4,5b 10.2 Hz, H-5b); 13C NMR (50
MHz, CDCl3): l 140.1 (Ar-C), 132.5 (Ar-CH),
131.0 (Ar-CH), 118.4 (Ar-C), 111.0 (CN), 87.6,
74.9, 71.7 (C-2, 3, 4), 61.3 (OMe), 53.7 (C-1),
33.1 (C-5); MS (CI, CH4): 298 (M+1), 280
(M−H2O), 163 (M−SC6H4CN), 145 (M−
SC6H4CN−H2O), 131 (M−SC6H4CN−
MeOH). Anal. Calcd for C13H15NO3S2
(297.38): C, 52.50; H, 5.08. Found: C, 52.77; H,
5.12.
1,5-dithio-i- -xylopyranoside (14): mp (from
D
EtOH) 135–136 °C, [h]2D0 +31° (c 0.17,
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.58
(m, 4 H, Ar), 5.16 (dd, 1 H, J1,2 10.6, J2,3 9.4
Hz, H-2), 4.95 (t, 1 H, J3,4 9.4 Hz, H-4), 4.16
(d, 1 H, H-1), 3.52 (m, 1 H, H-4), 3.40 (s, 3 H,
OMe), 2.86 (dd, 1 H, J4,5a 4.4, J5a,5b 13.6 Hz,
H-5a), 2.63 (dd, 1 H, J4,5b 10.9, H-5b), 2.06 (s,
3 H, CH3CO), 2.03 (s, 3 H, CH3CO); 13C
NMR (75 MHz, CDCl3): l 169.7 (CH3CO),
169.5 (CH3CO), 139.5 (Ar-C), 132.3 (Ar-CH),
131.0 (Ar-CH), 118.1 (Ar-C), 111.1 (CN),
80.5, 75.4, 73.4 (C-2, 3, 4), 57.9 (OMe), 50.5
(C-1), 31.0 (C-5), 20.6 (CH3CO), 20.4
(CH3CO); MS (EI): 381 (0.1, M+), 289 (1.0,
M−MeOH−AcOH), 187 (15.9, M−
SC6H4CN−AcOH),
145
(68.0,
M−
References
SC6H4CN−AcO−Ac), 43 (100, Ac). HRMS
Calcd for C17H19NO5S2: 381.0705. Found:
381.0690.
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4-Cyanophenyl 3-O-methyl-1,5-dithio-i- -
D
xylopyranoside (2).—To a suspension of the
triol 1 (820 mg, 2.9 mmol), and (PhBO)3 (317
mg, 0.35 equiv) in anhydrous toluene (40 mL)
[4] P.J. Garegg, B. Samuelsson, J. Chem. Soc., Perkin Trans.
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,
was added 2 g of crushed 4 A molecular
sieves, and the mixture was boiled under
reflux under argon for 20 h. Toluene was
evaporated off under diminished pressure, and
the crude product was used for next step
without purification.
[5] P.J. Garegg, B. Samuelsson, Synthesis, (1979) 813–814.
[6] (a) A.B. Foster, A.H. Haines, T.D. Inch, M.H. Randall,
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