Thiosugar nucleosides. Effect of sulfur in the synthesis of substituted azido-5-thio-D-gluco- and allopyranosyl-N-nucleosides and new isothionucleoside derivatives thereof

Article abstract of DOI:10.1081/CAR-200053715

1-(2,3,4-tri-O-acety-6-azido-6-deoxy-5-thio-β-D-glucopyranosyl)thymine 5 and the 6-thio-septanosylthymine analogue 7 were obtained via the intramolecular displacement of the corresponding tosylate 2 by azide. Alternatively, 5 was obtained from bromination of alcohol 1 in the presence of azide. Deblocking of 5 afforded the nucleoside 6. Glycosylation of the tetraacetate 11, obtained by acetolysis of 10 with thymine, afforded the 3-O-tosyl-β-D-glucopyranosylthymine derivative 13, which furnished the 3-azido-3-deoxy-β-D-allopyranosyl-thymine analogue 14 on reaction with azide ion. Alternatively, the glucoside 12 gave the corresponding gluco analogue 16 on treatment with azide. Acetolysis of 16 furnished the tetraacetate 17, which was subjected for glycosylation to give the gluco nucleoside 18. Deblocking of 14 and 18 afforded the free 3-azido-nucleosides 15 and 19, respectively. The isothionucleoside 21 was prepared from treatment of thymine with the 2,3-epoxide derivative 20 in the presence of Ti(i-PrO)₄ and triethyl amine. Mild acid hydrolysis of 21 afforded 22. Cycloaddition of the 2-azido-altroside 23 with dimethyl acetylenedicarboxylate gave the 1,2,3-triazole derivative 24. Treatment of 24 with methanolic ammonia afforded the 4,5-carboxamide analogue 25. The conformations of the new products were studied by NMR spectroscopy. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/CAR-200053715

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Thiosugar Nucleosides. Effect
of Sulfur in the Synthesis of
Substituted Azido‐5‐Thio‐D‐Gluco‐ and
Allopyranosyl‐N‐Nucleosides and New
Isothionucleoside Derivatives Thereof
Najim A. Al‐Masoudi a , Yaseen A. Al‐Soud b & Thilo Schuppler a
a Formerly Department of Chemistry , University of Konstanz ,
Konstanz, Germany
b Department of Chemistry, College of Science , University of Al
al‐Bayt , Al‐Mafraq, Jordan
Published online: 16 Aug 2006.
To cite this article: Najim A. Al‐Masoudi , Yaseen A. Al‐Soud & Thilo Schuppler (2005) Thiosugar
Nucleosides. Effect of Sulfur in the Synthesis of Substituted Azido‐5‐Thio‐D‐Gluco‐ and
Allopyranosyl‐N‐Nucleosides and New Isothionucleoside Derivatives Thereof, Journal of Carbohydrate
Chemistry, 24:3, 237-250, DOI: 10.1081/CAR-200053715
To link to this article: http://dx.doi.org/10.1081/CAR-200053715
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Journal of Carbohydrate Chemistry, 24:237–250, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1081/CAR-200053715
Thiosugar Nucleosides.
Effect of Sulfur in the
Synthesis of Substituted
Azido-5-Thio-D-Gluco- and
Allopyranosyl-N-
Nucleosides and New
Isothionucleoside
Derivatives Thereof
Najim A. Al-Masoudi
Formerly Department of Chemistry, University of Konstanz, Konstanz, Germany
Yaseen A. Al-Soud
Department of Chemistry, College of Science, University of Al al-Bayt,
Al-Mafraq, Jordan
Thilo Schuppler
Formerly Department of Chemistry, University of Konstanz, Konstanz, Germany
1-(2,3,4-tri-O-acety-6-azido-6-deoxy-5-thio-b-D-glucopyranosyl)thymine
5
and the
6-thio-septanosylthymine analogue 7 were obtained via the intramolecular displace-
ment of the corresponding tosylate 2 by azide. Alternatively, 5 was obtained from bromi-
nation of alcohol 1 in the presence of azide. Deblocking of 5 afforded the nucleoside 6.
Glycosylation of the tetraacetate 11, obtained by acetolysis of 10 with thymine,
afforded the 3-O-tosyl-b-D-glucopyranosylthymine derivative 13, which furnished the
3-azido-3-deoxy-b-D-allopyranosyl-thymine analogue 14 on reaction with azide ion.
Alternatively, the glucoside 12 gave the corresponding gluco analogue 16 on treatment
Received August 10, 2004; accepted January 18, 2005.
Address correspondence to Najim A. Al-Masoudi, P.O. Box 100552, D-78405 Konstanz,
Germany. E-mail: najim.al-masoudi@gmx.de
237

N. A. Al-Masoudi, Y. A. Al-Soud, and T. Schuppler
238
with azide. Acetolysis of 16 furnished the tetraacetate 17, which was subjected for gly-
cosylation to give the gluco nucleoside 18. Deblocking of 14 and 18 afforded the free
3-azido-nucleosides 15 and 19, respectively. The isothionucleoside 21 was prepared
from treatment of thymine with the 2,3-epoxide derivative 20 in the presence of Ti(i-
PrO)4 and triethyl amine. Mild acid hydrolysis of 21 afforded 22. Cycloaddition of the
2-azido-altroside 23 with dimethyl acetylenedicarboxylate gave the 1,2,3-triazole
derivative 24. Treatment of 24 with methanolic ammonia afforded the 4,5-carboxamide
analogue 25. The conformations of the new products were studied by NMR spectroscopy.
Keywords Biological
activity,
Glycosylation,
Epimerization,
Nucleosides,
Isothionucleosides
INTRODUCTION
Nucleosides wherein the furanoside ring oxygen is replaced by sulfur were
first described in the 1960s and were shown to have interesting biological
activity.[1–6] Among these are the 40-thio analogues of azidothymidine (AZT),
dideoxyinosine, dideoxycytidine, (E)-5-(2-bromovinyl)-20-deoxyuridine, and
the 40-thio analogues of the naturally occuring 20-deoxynucleosides of which
some have antiviral activity.[7–10] On the other hand, several laboratories[11–
19]
have described various 40-thio analogues of purine and pyrimidine nucleo-
sides with some remarkable potency against herpes simplex virus type 1
(HSV-1) and varicella zoster virus, but associated with high toxicity. To date,
only the thionucleoside b-L-(-)-20-deoxy-30-thiacytidine[20] (lamivudine,
3TCTM) has been licensed by the American Food and Drug Administration as
both an anti-AIDS and an antihepatitis drug, since the 50-O-carbamate deriva-
tives[21] are found to be active against human immundiffiency virus type 1
(HIV-1) as well as human hepatitis B virus (HBV). Recently, we have reported
the synthesis of nucleosides from 5-thio-D-xylose,[22] 5-thio-D-glucose,[23] and
a-D,L-arabino-pentulopyranosyl derivatives.[24] The most significant attempts
are the introduction of the bioactive azide or amino groups in these thionucleo-
sides by substituting the OH-6 group or changing the chirality of the pyranosyl
moiety at C-3 with an azido group, which might lead to potentially active can-
didates in comparison to the anti-HIV drug AZT and its derivatives.[25] We
report here the synthesis of a new type of azido-thionucleosides carrying a
5-thio-b-D-glucopyranosyl moiety via sulfur participation and nucleophilic dis-
placement, as well as some novel iso-thionucleosides. We have selected 5-thio-D-
glucose[26] it acts as an active antimetabolite and exhibited interesting
biological activities, such as inhibition of spermatogenesis.[27]
RESULTS AND DISCUSSION
In earlier papers[28,29] it has been reported that nucleophilic displacement of 2-
or 4-O-sulfonates of 5-thiopyranoside derivatives proceeded via transannular

Thiosugar Derivatives
239
sulphur participation, giving substituted products with retention of configur-
ation or with ring contraction. Similarly,[30] a C-6-O-sulfonate of 5-thiopyrano-
side derivative a gave two products, the 6-substituted-5-thiopyranoside (c) and
the corresponding 6-thioseptanoside d. It was suggested that these reactions
proceeded via intermediate episulfonium ions b resulting from neighboring
group participation from the ring sulphur atom (Sch. 1).
The nucleoside 3 was prepared from the readily available nucleoside 1 in
two steps via the sulphonate ester 2.[31] When 3 was stirred with lithium
azide in dimethylformamide, two compounds were identified and separated
by chromatography. In the NMR spectrum of the first isomeric product, H-10
0
0
appeared as a doublet at d 5.62 with a large J1 ,2 value (9.1 Hz), indicating
the b-configuration, while other sugar protons H-20 –H-50 were fully assigned.
Furthermore, the observed NOE interactions between H-6 and both H-20
and H-40 and one of the two protons at C-60 doubtlessly indicated the
b-configuration. The compound was tentatively identified as 6-thio-a-L-idosep-
tanosyl)thymine derivative 7 in 37% yield. The second eluted product was
identified as 5-thio-b-D-glucopyranosyl)thymine derivative 5 in 57% yield,
which is consistent with the structure of a 5-thioglucopyrosides derivative pre-
viously prepared in our laboratory.[31] The 1H-NMR spectrum of 5 showed
0
0
0
0
0
0
0
0
large values of J1 ,2 ¼ 9.0 Hz; J2 ,3 ¼ J3 ,4 9.5 Hz, J4 ,5 ¼ 10.0 Hz, indicative
for the b-configuration and 4C1-conformation of the sugar moiety. The
proposed mechanism of formation of 5 and 7 might be explained in terms of
opening of the episulphonium ion 4, by azide ions via both routes a and b
(Sch. 2). The reactivity of azide ion favors an “SN2-like” attack at the
primary C-6, thus explaining the formation of 5 as a major product. On the
Scheme 1

N. A. Al-Masoudi, Y. A. Al-Soud, and T. Schuppler
240
Scheme 2: Reagents and conditions: (i) TsCl-pyridine, 238C, 16 hr; (ii) Ac2O-pyridine, 238C,
24 hr; (iii) LiN3, DMF, 1208C, 6 hr; (iv) NaOMe-MeOH, 238C, 16 hr; (v) Ph3P, NBS, DMF, 558C, 2 hr;
(vi) NaN3, 808C, 5 hr.
other hand, there is a possibility of formation of the intermediate 8, which
would lead to 5 in the presence of azide ions. Deblocking of 5 with sodium meth-
oxide in methanol afforded, after chromatographic purification, 6 in 79% yield.
Alternatively, 5 was prepared from 1 in 39% yield, according to the literature
procedure,[32] by reaction with triphenylphosphine and N-bromosuccinimide
in dimethylformamide at 558C, followed by reaction with azide ions at 808C.
The low yield of 5 might be explained in terms of addition of the azide group
to the thymine ring, in comparison to the results obtained recently by Kumer
et al.,[33] during the formation of 9 (Sch. 2).

Thiosugar Derivatives
241
Next, we examined the epimerization of an O-sulphonate at C-3 of the
gluco isomer of the nucleoside analogues by nucleophilic displacement by
the azide ions. Thus, glycosylation of the silylated thymine, devised by
Vorbru¨ggen et al.[34] with 11, obtained from acetolysis of 10 in 73% yield
under trimethylsilyl triflate (TMSOTf) catalysis furnished, after chromato-
graphic purification, 13 in 76% yield. Reaction of 13 with sodium azide in
boiling dimethylformamide gave, after chromatography, the expected allo-
azide 14 in 15% yield. Two minor products also formed, namely the unsatu-
rated nucleosides 3- and 4-deoxy-5-thio-D-hexen-enopyranosyl-thymines. The
1
structures of 13 and 14 were followed from their H NMR spectra.
0
0
The spectrum of 13 revealed large JH,H coupling values (J1 ,2
¼
0
0
0
0
0
0
J2 ,3 ¼ 9.4 Hz, J3 ,4 ¼ 9.5 Hz, J4 ,5 ¼ 10.0 Hz), indicative of the b-configuration
and the 4C1-conformation of the sugar moiety. The spectrum of 14 showed only
0
0
0
0
two large JH,H couplings (J1 ,2 ¼ 9.1 Hz, J4 ,5 ¼ 10.0 Hz) in keeping with an
4
b-allopyranosylthymine in the C1 conformation (Sch. 3). These results are
consistent with our previously reported results[35] during the nucleophilic dis-
placement of the sulphonate ester by the azide ions. Deblocking of 14 with
sodium methoxide in methanol procceded smoothly to give 15 in 85% yield.
Scheme 3: Reagents and conditions: (i) Ac2O-HOAc-H2SO4, 238C, 2hr; (ii) silyl. thymine,
TMSOTf, (CH2)2Cl2, 238C, 3 hr; (iii) LiN3, DFM, reflux, 7 hr; (iv) NaOMe-MeOH, 238C 16 hr.

N. A. Al-Masoudi, Y. A. Al-Soud, and T. Schuppler
242
Alternatively, heating of 12 with sodium azide in dimethylformamide
afforded 16 as the main product and isolated as the syrupy tetraacetate
17[35] after acetolysis. The formation of 16 can be explained as a result of
double inversion, where 12 is converted first into the allo-epoxide, which
then underwent azide ion opening,[36] leading mainly to 16. Condensation of
the silylated thymine, devised by Vorbru¨ggen et al.,[34] with 17 in the
presence of TMSOTf as a catalyst gave, after chromatographic purification,
18 in 72% yield. Deblocking of 18 with sodium methoxide in methanol
furnished 19 in 83% yield. The structures of 18 and 19 were confirmed by
1
0
0
their H NMR and mass spectra. The large value of J1 ,2 (9.1 Hz and 10.0 Hz,
respectively), is indicative for the b-configuration, while the large couplings
0
0
0
0
0
0
of J2 ,3 ¼ 10.0 Hz, J3 ,4 ¼ 9.5 Hz, J4 ,5 ¼ 10.0 Hz, respectively, confirmed the
4C1 conformation of the sugar moiety.
By emplyoing Lopez’ procedure,[37] 20 was subjected for opening of the 2,3-
epoxy ring by the azide ions, using titanium tetraisopropoxide [Ti(i-PrO)4] as a
Lewis acid catalyst in the presence of triethyl amine (Sch. 4) to afford 21 in 52%
yield. Although the altro isomer favors the 1C4 conformation, the 1H NMR data
4
confirmed that 21 existed mainly in the C1 conformation, due to the trans-
fused 4,6-O-isopropylidene ring. Mild acid hydrolysis of 21 with 80% acetic
acid afforded 22 in 83% yield, which the 1H NMR spectrum suggested to
4
exist mainly in the C1 conformation. These data are consistent with those of
the altroside derivatives reported previously.[38]
The significant cytotoxic properties and anticancer activity of several tria-
zolated compounds prompted us to synthesize a new 1,2,3-triazole derivative of
a 5-thio-altro-isonucleoside by employing our recent synthetic approaches[39]
starting from 23, prepared previously in our laboratory.[38] Thus, reaction of
23 (Sch. 5) with dimethyl acetylenedicarboxylate (DMAD) furnished 24
(74%) and subsequently gave the 4,5-dicarboxamide derivative 25 (84%) on
treatment with 16% methanolic ammonia. The structures of 24 and 25 were
identified from their 1H NMR and mass spectra. Although 24 existed in equili-
4
1
brium between C1 and C4 conformations as proved previously,[39] the large
0
0
J4 ,5 values (10.3 Hz, and 9.5 Hz, respectively) and low coupling values of the
Scheme 4

Thiosugar Derivatives
243
;;
Scheme 5: Reagents and conditions: (i) MeO2C– –CO2Me; toluene, 608C; (ii) NH3/MeOH,
238C, 16 hr.
4
other sugar protons indicated that both 24 and 25 preferred the C1 confor-
mation, possibly due to the repulsion between the triazole ring at C-20 and
1
OMe at C-10 in the case of the C4 conformation, as shown in Scheme 5.
EXPERIMENTAL
General
See references [24,39].
Reaction of 1-(1,2,4,6-tetra-O-acetyl-3-O-toluene-p-sulphonyl-5-thio-D-
glucopyranosyl) thymine (3) with azide ions. A solution of 3[31]
(500 mg, 0.86 mmol) in dimethylformamide (15 mL) was stirred with lithium
azide at 238C for 16 hr. After cooling, the mixture was evaporated to dryness
and the residue was partitioned between chloroform (30 mL) and water
(4 ꢀ 20 mL). The organic extract was dried (Na2SO4), filtered, and evaporated
to dryness to give a foam, which was chromatographed on a silical gel column
(50 g). Elution with dichloromethane and methanol (0–3%) gave first a
foam identified as 1-(2,3,4-tri-O-acety-5-azido-5-deoxy-6-thio-a-L-idopsepta-
nosyl)thymine (7, 145 mg, 37%). 1H NMR (CDCl3): d 6.56 (s, 1H, H-6),
5.62 (d, 1H, J1 ,2 ¼ 9.1 Hz, H-10), 5.42 (dd, 1H, J2 ,3 ¼ 8.4 Hz, H-20), 5.21
0
0
0
0
(dd, 1H, J3 ,4 ¼ 6.0 Hz, H-40), 5.01 (dd, 1H, J4 ,5 ¼ 2.6 Hz, H-40), 3.53
0
0
0
0
(ddd, 1H, J5 ,6 a ¼ 5.8 Hz, H-50), 2.65 (dd, 1H, J5 ,6 b ¼ 2.7 Hz, H-60b), 2.32 (dd,
0
0
0
0
1H, J6 a,6 b ¼ 13.0 Hz, H-60a), 2.09, 1.96, 1.86 (3 ꢀ s, 9H, 3 ꢀ OAc), 1.93
0
0

N. A. Al-Masoudi, Y. A. Al-Soud, and T. Schuppler
244
(s, 3H, C5-Me). Anal. Calcd C17H21N5O8S (455.45): C, 44.83; H, 4.65; N, 15.38.
Found: C, 44.51; H, 4.54; N, 15.19. MS: m/z (FAB) 456 (M þ Hþ). Further
elution gave an amorphous solid identified as 1-(2,3,4-tri-O-acety-6-azido-6-
1
deoxy-5-thio-b-D-glucopyranosyl)thymine (5, 223 mg, 57%). H NMR (CDCl3):
10.12 (s, 1H, NH), 7.54 (s, 1H, H-6), 5.84 (d, 1H, J1 ,2 ¼ 9.0 Hz, H-10), 5.70
0
0
(t, 1H, J2 ,3 ¼ 9.0 Hz, H-20), 5.29 (dd, 1H, J3 ,4 ¼ 9.5 Hz, H-30), 5.12 (dd, 1H,
0
0
0
0
J4 ,5 ¼ 10.0 Hz, H-40), 3.50 (ddd, 1H, J5 ,6 b ¼ 3.3 Hz, H-50), 3.41 (dd, 1H,
0
0
0
0
J5 ,6 a ¼ 6.0 Hz, H-60a), 3.30 (dd, 1H, J6 a,6 b ¼ 13.5 Hz, H-60b), 2.08, 1.96, 1.87
(3 ꢀ s, 9H, 3 ꢀ OAc), 1.91 (s, 3H, C5-Me). Anal. Calcd C17H21N5O8S (455.45),
C, 44.83; H, 4.65; N, 15.38. Found: C, 44.42; H, 4.57; N, 15.18. MS: m/z
(FAB) 456 (MHþ).
0
0
0
0
1-(6-Azido-6-deoxy-5-thio-b-D-glucopyranosyl)thymine (6).
a. A solution of 5 (300 mg, 0.66 mmol) in 0.3 M sodium methoxide (10 mL)
was stirred at 238C for 16 hr. The solution was neutralized with acetic acid to
pH 5, then evaporated to dryness, and the residue was partitioned between
water (15 mL) and ether (3 ꢀ 15 mL). The aqueous layer was evaporated
to dryness, and the residue was coevaporated with ethanol (3 ꢀ 10 mL)
and then crystallized from ethanol to give 6 (172 mg, 79%) as a solid,
m.p. 157–1628C. 1H NMR (DMSO-d6/D2O): d 7.51 (s, 1H, H-6), d 5.47
(d, 1H, J1 ,2 ¼ 9.5 Hz, H-10), 3.87 (dd, 1H, J6 a,6 b ¼ 13.0 Hz, H-60b), 3.74
0
0
0
0
(dd, 1H, J5 ,6 a ¼ 6.2 Hz, H-60a), 3.71 (t, 1H, J2 ,3 ¼ 9.5 Hz, H-20), 3.07 (t, 1H,
0
0
0
0
J3 ,4 ¼ 9.2 Hz, H-30), 3.29 (dd, 1H, J4 ,5 ¼ 9.6 Hz, H-40), 2.94 (ddd, 1H,
0
0
0
0
J5 ,6 b ¼ 2.4 Hz, H-50), 1.90 (s, 3H, C5-Me). Anal. Calcd for C11H15N5O5S
(329.33), C, 40.12; H, 4.59; N, 21.27. Found: C, 39.91; H, 4.46; N, 21.05. MS:
m/z (FAB) 352 (M þ Naþ).
0
0
b. To a cooled solution of 1 (350 mg, 1.15 mmol), and triphenyl phosphine
(0.61 g, 2.30 mmol) in dry dimethylformamide (7.0 mL) was added N-
bromosuccinimide (NBS, 0.40 g, 2.23 mmol), and the solution was heated for
2 hr at 558C with stirring. After cooling, methanol (0.5 mL) was added to decom-
pose the excess of NBS, followed by addition of sodium azide (1.30 g, 2.00 mmol).
The suspension was heated for 5 hr at 808C, with stirring. After cooling, the
solvent was evaporated to dryness, and the residue was partitioned between
water (30 mL) and 1:1 choloroform-hexane (3 ꢀ 15 mL). The water phase was
evaporated to dryness, and the residue was coevaporated with methanol with
1.0 g of silica gel and then poured onto a column of silica gel. Elution with
dichoromethane and methanol (0–10%) afforded 6 (0.30 g, 39%) as a solid.
The physical data were identical to the authentic sample prepared by method a.
1,2,4,6-Tetra-O-acetyl-3-O-toluene-p-sulphonyl-5-thio-D-glucopyranose
(11). To a solution of 10[40] (300 mg, 0.61 mmol) in acetic acid (1.0 mL) and
acetic anhydride (2.0 mL) was added sulphuric acid (0.1 mL) at 08C, and the
mixture was kept at 238C for 2 d. A dil. solution of sodium bicarbonate

Thiosugar Derivatives
245
(15 mL) was added, and the mixture was stirred for 30 min followed by addition
of water (10 mL). The mixture was partitioned between dichloromethane
(30 mL) and sodium bicarbonate solution (3 ꢀ 15 mL), and the organic layer
was washed with water (20 mL), dried (Na2SO4), filtered, and evaporated to
dryness. The oily residue was chromatographed on silica gel, (7 g), using
toluene-ethyl acetate (7:3) as eluent to give 11 (241 mg, 73%) as a syrup.
1H NMR (CDCl3): d 6.12 (d, 1H, J1 ,2 ¼ 9.4 Hz, H-10), 5.60–5.14 (m, 3H, H-20,
0
0
H-30, H-40), 4.40 (dd, 1H, J5 ,6 a ¼ 4.7 Hz, H-60a), 4.20 (dd, 1H, J6 a,6 b ¼12.0 Hz,
0
0
0
0
H-60b), 3.42 (ddd, 1H, J5 ,6 b ¼ 3.5 Hz, H-50), 2.45 (s, 3H, ArMe), 2.19, 2.17,
0
0
2.09, 2.00 (4 ꢀ s, 12H, 4 ꢀ OAc). MS: (C21H26O11S2) m/z (FAB) 541 (M þ Na)þ.
1-(2,4,6-Tri-O-acetyl-3-O-toluene-p-sulphonyl-5-thio-b-D-glucopyrano
syl)thymine (13). A suspension of thymine (360 mg, 2.88 mmol) in hexam-
ethyldisilazane (10 mL) containing a few crystals of ammonium sulphate was
boiled for 5 hr. After cooling, a solution of 11 (700 mg, 0.96 mmol) in dry
dichloroethane (15 mL) was added to the clear solution of the silylated
thymine, followed by the addition of the trimethylsilyl trifluoromethanesulfo-
nate (0.1 mL), with stirring. After 3 hr, the solution was evaporated to
dryness and the residue was partitioned between dicholoromethane (35 mL)
and a dil. solution of sodium bicarbonate (3 ꢀ 15 mL), and the organic layer
was washed with water (20 mL), dried (Na2SO4), filtered, and evaporated to
dryness. The residue was poured onto a column of silica gel (20 g) and eluted
with dicholoromethane and methanol (0–0.2%) to give 13 (426 mg, 76%) as a
1
solid, m.p. 162–1668C. H NMR (CDCl3): d 10.70 (s, 1H, NH), 7.57 (s, 1H,
H-6), 5.84 (d, 1H, J1 ,2 ¼ 9.4 Hz, H-10), 5.68 (t, 1H, J3 ,4 ¼ 9.5 Hz, H-30), 5.59
0
0
0
0
(t, 1H, J2 ,3 ¼ 9.4 Hz, H-20), 5.17 (dd, 1H, J4 ,5 ¼ 10.0 Hz, H-40), 4.28 (dd, 1H,
0
0
0
0
J5 ,6 a ¼ 4.5 Hz, H-60a), 4.10 (dd, 1H, J6 a,6 b ¼ 12.0 Hz, H-60b), 3.39 (ddd,
0
0
0
0
1H, J5 ,6 b ¼ 3.5 Hz, H-50), 2.40 (s, 3H, MeAr), 2.10, 2.04, 1.96 (3 ꢀ s, 9H,
3 ꢀ OAc), 1.94 (s, 3H, C5-Me). Anal. Calcd. for C24H28N2O11S2 (584.62):
C, 49.62; H, 4.83; N, 4.79. Found: C, 49.41; H, 4.68; N, 4.49. MS: m/z (FAB)
585 (M þ H)þ.
0
0
1-(2,4,6-Tri-O-acetyl-3-azido-3-deoxy-5-thio-b-D-allopyranosyl)thymine
(14). A solution of 13 (570 mg, 0.97 mmol) in dimethylformamide (15 mL) con-
taining lithium azide (131 mg, 2.91 mmol) was heated under reflux for 7 hr,
then concentrated in vacuo. The residue was partitioned between water
(20 mL) and dicholoromethane (3 ꢀ 15 mL), and the combined organic
extracts were dried (Na2SO4), filtered, and evaporated to dryness. The
residue was poured onto a column of silica gel (20 g) and eluted, in gradient,
with methanol (0–0.3%) and dichloromethane. The last fractions were tenta-
1
tively identified as 14 (66 mg, 15%) as amorphous solid. H NMR (CDCl3): d
10.21 (s, 1H, NH), 7.56 (s, 1H, H-6), 5.81 (d, 1H, J1 ,2 ¼ 9.1 Hz, H-10), 5.60
0
0
(dd, 1H, J4 ,5 ¼ 10.0 Hz, H-40), 4.15 (dd, 1H, J2 ,3 ¼ 4.1 Hz, H-20), 3.97 (dd,
0
0
0
0

N. A. Al-Masoudi, Y. A. Al-Soud, and T. Schuppler
246
1H, J3 ,4 ¼ 5.1 Hz, H-30), 4.28 (dd, 1H, J5 ,6 a ¼ 5.0 Hz, H-60a), 4.08 (dd, 1H,
0
0
0
0
J6 a,6 b ¼ 12.0 Hz, H-60b), 3.36 (ddd, 1H, J5 ,6 b ¼ 4.0 Hz, H-50), 2.14, 2.13, 2.12
(3 ꢀ s, 9H, 3 ꢀ OAc), 1.93 (s, 3H, C5-Me). Anal. Calcd for C17H21N5O8S
(455.45): C, 44.83; H, 4.65; N, 15.38. Found: C, 44.62; H, 4.53; N, 15.01. MS:
m/z (FAB) 456 (M þ H)þ.
0
0
0
0
1-(3-Azido-3-deoxy-5-thio-b-D-allopyranosyl)thymine (15). A solution of
14 (50 mg, 0.11 mmol) in 0.3 M sodium methoxide (5 mL) was stirred at 238 for
16 hr, then worked up as in 6, to give 15 (31 mg, 85%) as a solid, m.p. 135–
1398C. 1H NMR (DMSO-d6/D2O):
d
7.56 (s, 1H, H-6), 5.49 (d, 1H,
J1 ,2 ¼ 9.0 Hz, H-10), 4.03 dd, 1H, J2 ,3 ¼ 5.0 Hz, H-30), 3.80 (dd, 1H, J5 ,6 a
¼
0
0
0
0
0
0
5.1 Hz, H-60a), 3.41 (dd, 1H, J2 ,3 ¼ 4.1 Hz, H-20), 3.39 (dd, 1H, J6 a,6 b ¼ 12.0 Hz,
0
0
0
0
H-60b), 3.29 (dd, 1H, J4 ,5 ¼ 10.5 Hz, H-40), 2.75 (ddd, 1H, J5 ,6 b ¼ 4.0 Hz, H-50),
1.92 (s, 3H, C5-Me). Anal. Calcd for C11H15N5O5S (329.33): C, 40.12; H, 4.59; N,
21.27. Found: C, 39.96; H, 4.4.7; N, 20.95. MS: m/z (FAB) 352 (M þ Na)þ.
0
0
0
0
1-(2,4,6-Tri-O-acetyl-3-azido-3-deoxy-5-thio-b-D-glucopyranosyl)thymine
(18). A suspension of thymine (650 mg, 5.20 mmol) in hexamethyldisilazane
(20 mL) containing a few crystals of ammonium sulphate was heated under
reflux for 5 hr. After cooling, a solution of 17[35] (680 mg, 1.74 mmol) in dry
dichloroethane (15 mL) was added, followed by the addition of the trimethylsi-
lyl trifluoromethanesulfonate (0.1 mL), with stirring. After 3 hr, the solution
was evaporated to dryness, and the residue was partitioned between dichloro-
methane (35 mL) and a dil. solution of sodium bicarbonate (3 ꢀ 15 mL), and the
organic layer was washed with water (20 mL), dried (Na2SO4), filtered, and
evaporated to dryness. The residue was poured onto a column of silica gel
(20 g) and eluted, in gradient, with methanol (0–0.2%) and dichloromethane
to give 18 (570 mg, 72%) as amorphous solid. 1H NMR (CDCl3): d 10.32
(s, 1H, NH), 7.56 (s, 1H, H-6), 5.92 (d, 1H, J1 ,2 ¼ 9.1 Hz, H-10), 5.44 (t, 1H,
0
0
J2 ,3 ¼ 10.0 Hz, H-20), 4.48 (t, 1H, J4 ,5 ¼ 10.0 Hz, H-40), 4.26 (dd, 1H, J5 ,6 a
¼
0
0
0
0
0
0
5.0 Hz, H-60a), 4.11 (dd, 1H, J6 a,6 b ¼ 12.0 Hz, H-60b), 3.74 (t, 1H,
0
0
J3 ,4 ¼ 10.0 Hz, H-30), 3.56 (ddd, 1H, J5 ,6 b ¼ 3.5 Hz, H-50), 2.10, 1.98, 1.88
(3 ꢀ s, 9H, 3 ꢀ OAc), 1.92 (s, 3H, C5-Me). Anal. Calcd for C17H21N5O8S
(455.45): C, 44.83; H, 4.65; N, 15.38. Found: C, 44.542; H, 4.55; N, 15.09. MS:
m/z (FAB) 456 (M þ H)þ.
0
0
0
0
1-(3-Azido-3-deoxy-5-thio-b-D-glucopyranosyl)thymine (19). A solution
of 18 (200 mg, 0.44 mmol) in 0.3 M sodium methoxide (10 mL) was stirred
at 238C for 16 hr, then worked up as in 6, to give 19 (120 mg, 83%) as a
1
solid, m.p. 141–1458C. H NMR (DMSO-d6/D2O): d 7.56 (s, 1H, H-6), 5.52
(d, 1H, J1 ,2 ¼ 10.0 Hz, H-10), 3.90 (t, 1H, J2 ,3 ¼ 9.5 Hz, H-30), 3.74 (dd, 1H,
0
0
0
0
J5 ,6 a ¼ 5.0 Hz, H-60a), 3.70 (t, 1H, J2 ,3 ¼ 9.5 Hz, H-20), 3.37 (dd, 1H, J6 a,6 b
¼
0
0
0
0
0
0
12.0 Hz, H-60b), 3.42 (dd, 1H, J4 ,5 ¼ 10.0 Hz, H-40), 2.94 (ddd, 1H,
0
0

Thiosugar Derivatives
247
J5 ,6 b ¼ 4.0 Hz, H-50), 1.92 (s, 3H, C5-Me). Anal. Calcd for C11H15N5O5S
(329.33): C, 40.12; H, 4.59; N, 21.27. Found: C, 39.83; H, 4.4.5; N, 20.89. MS:
m/z (FAB) 452 (M þ Na)þ.
0
0
Reaction of the anhydro derivative 20 with thymine (synthesis of iso-
thionucleoside). To a solution of 20[41] (400 mg, 1.72 mmol) in dichloro-
methane (15 mL) contaning triethyl amine (2 mL) was added Ti(i-PrO)4
(142 mg, 0.50 mmol), and the mixture was boiled for 6 hr. After cooling, the
solution was evaporated to dryness, and the residue was partitioned between
water (15 mL) and dichloromethane (3 ꢀ 20 mL). The combined organic
extracts were dried (Na2SO4), filtered and evaporated to dryness, and the
residue was chromatographed on silica gel (20 g). Elution, in gradient, with
methanol (0–0.5%) and dichloromethane afforded an amorphous solid, ident-
ified as 1-(methyl-4,6-O-isopropylidene-5-thio-a-D-altropyranosid-2-yl)thy-
mine (21) (320 mg, 52%). 1H NMR (CDCl3): d 7.58 (s, 1H, H-6), 4.84
(t, 1H, J2 ,3 ¼ 3.5 Hz, H-20), 4.41 (d, 1H, J1 ,2 ¼ 2.8 Hz, H-10), 4.17 (dd, 1H,
0
0
0
0
J4 ,5 ¼ 9.5 Hz, H-40), 4.02 (dd, 1H, J3 ,4 ¼ 2.8 Hz, H-30), 3.82 (dd, 1H,
0
0
0
0
J5 ,6 a ¼ 6.5 Hz, H-60a), 3.78 (dd, 1H, J6 a,6 b ¼ 11.3 Hz, H-60b), 3.49 (ddd,
0
0
0
0
1H, J5 ,6 b ¼ 10.5 Hz, H-50), 3.23 (s, 3H, OMe), 2.27 (t, 1H, J3,OH ¼ 5.0 Hz,
C3-OH), 1.92 (s, 3H, C5-Me), 1.54, 1.46 (2 ꢀ s, 6H, CMe2). Anal. Calcd for
C15H22N2O6S (358.41): C, 50.27; H, 6.19; N, 7.82. Found: C, 50.02; H, 6.04;
N, 7.57. MS: m/z (FAB) 359 (M þ Hþ.
0
0
1-(Methyl-5-thio-b-D-altropyranosid-2-yl)thymine (22). A solution of 21
(250 mg, 0.70 mmol) in 80% acetic acid (4 mL) was left at 238C for 16 hr and
then was evaporated to dryness. The residue was coevaporated with ethanol
(4 ꢀ 10 mL), and the residue was poured onto a column of silica gel (1.0 g).
Elution, in gradient, with methanol (0–10%) and dichloromethane gave 22
1
(208 mg, 83%) as amorphous solid. H NMR (DMSO-d6/D2O): d 7.59 (s, 1H,
H-6), 4.59 (d, 1H, J1 ,2 ¼ 4.0 Hz, H-10), 4.09 (dd, 1H, J4 ,5 ¼ 9.4 Hz, H-40),
0
0
0
0
3.93 (dd, 1H, J5 ,6 a ¼ 4.5 Hz, H-60a), 3.89 (dd, 1H, J3 ,4 ¼ 4.7 Hz, H-30), 3.80
0
0
0
0
(dd, 1H, J6 a,6 b ¼ 11.7 Hz, H-60b), 3.35 (ddd, 1H, J5 ,6 b ¼ 5.5 Hz, H-50), 1.93
(s, 3H, C5-Me). Anal. Calcd for C12H18N2O6S (318.35): C, 45.27; H, 5.70; N,
8.80. Found: C, 45.96; H, 5.57; N, 8.51. MS: m/z (FAB) 341 (M þ Naþ).
0
0
0
0
Dimethyl-1-(methyl-3,4,6-tri-O-acetyl-5-thio-a-D-glucopyranosid-2-yl)-
1,2,3-triazole-4,5-dicarboxylate (24). To a solution of 23[38] (600 mg,
1.66 mmol) in dry toluene (20 mL) was added dimethyl-acetylenedicarboxylate
(3 mL, in excess), and the reaction mixture was stirred at 808C under nitrogen
for 24 hr. After cooling, the solution was evaporated to dryness, and the residue
was partioned between dichloromethane (3 ꢀ 25 mL) and water (30 mL). The
combined organic extracts were dried (Na2SO4), filtered and evaporated to
dryness, and the residue was chromatographed on a column of silica gel

N. A. Al-Masoudi, Y. A. Al-Soud, and T. Schuppler
248
(20 g). Elution, in gradient, with methanol (0–0.2%) and dichloromethane
afforded 24 (618 mg, 74%), as amorphous solid. 1H NMR (CDCl3): d 7.58
(s, 1H, H-6), 5.38 (dd, 1H, J4 ,5 ¼ 10.3 Hz, H-40), 5.20 (dd, 1H, J3 ,4 ¼ 3.0 Hz,
0
0
0
0
H-30), 4.79 (dd, 1H, J2 ,3 ¼ 3.7 Hz, H-20), 4.35 (d, 1H, J1 ,2 ¼ 2.6 Hz, H-10), 4.40
0
0
0
0
(dd, 1H, J5 ,6 a ¼ 3.4 Hz, H-60a), 4.11 (dd, 1H, J6 a,6 b ¼ 12.0 Hz, H-60b), 4.01,
0
0
0
0
3.97 (2 ꢀ s, 6H, 2 ꢀ COMe), 3.70 (s, 3.70 (ddd, 1H, J5 ,6 b ¼ 5.2 Hz, H-50), 3.47
0
0
0
(C1 -OMe), 2.10, 2.06, 2.00 (3 ꢀ s, 9H, 3 ꢀ OAc). Anal. Calcd for
C19H25N3O11S (503.48): C, 45.33; H, 5.00; N, 8.35. Found: C, 45.04; H, 4.87;
N, 7.95. MS: m/z (FAB) 504 (M þ Hþ).
1-(Methyl-5-thio-a-D-glucopyranosid-2-yl)-1,2,3-triazole-4,5-dicarbox
amide (25). A solution of 24 (250 mg, 0.49 mmol) in 16% methanolic
ammonia (7 mL) was stirred at 238C for 18 hr, then the reaction mixture was
evaporated to dryness. The residue was partitioned between water (10 mL)
and ether (3 ꢀ 10 mL), and the aqueous layer was evaporated to dryness.
The residue was coevaporated with ethanol (4 ꢀ 10 mL), then recrystallized
1
from ethanol to give 25 (143 mg, 84%) as a solid, m.p. 136–1408C. H NMR
(DMSO-d6/D2O): d 7.57 (s, 1H, H-6), 4.47 (d, 1H, J1 ,2 ¼ 3.9 Hz, H-10), 4.32
0
0
(dd, 1H, J2 ,3 ¼ 5.0 Hz, H-20), 3.96 (dd, 1H, J4 ,5 ¼ 9.5 Hz, H-40), 3.90 (dd, 1H,
0
0
0
0
J5 ,6 a ¼ 4.3 Hz, H-60a), 3.80 (dd, 1H, J3 ,4 ¼ 3.3 Hz, H-30), 3.75 (dd, 1H,
0
0
0
0
J6 a,6 b ¼ 12.0 Hz, H-60b), 3.34 (ddd, 1H, J5 ,6 b ¼ 5.7 Hz, H-50). Anal. Calcd for
C11H17N5O6S (347.37): C, 38.04; H, 4.93; N, 20.16. Found: C, 37.86; H, 4.78;
N, 19.89. MS: m/z (FAB) 370 (M þ Naþ).
0
0
0
0
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