Some 2′-modified 4′-thionucleosides via sulfur participation and synthesis of Thio-AZT from 4′-thiofuranoid 1,2-glycal

Article abstract of DOI:10.1080/10426500307902

ThioAZT 14 was synthesized in eight steps from D-arabinose derivative 4 via the new thiofuranoid 1,2-glycal, 5-O-Acetyl-1,2,4-trideoxy-1,4-epithio-3-O-p-toluenesulfonyl-D-threo-pent-1- enitol (8). Ribosylation of the thiosugar 6 with thymine afforded regioselectively the nucleoside 16. Treatment of 16 with sodium azide in hot DMF gave, after spontaneous intramolecular displacment, the 2′-azido-xylo derivative 18, which furnished the free nucleoside 19 on treatment with methanolic ammonia. Similarly, treatment of 16 with sodium ethylthiolate in boiling methanol led to inversion in configuration and gave, after several intramolecular displacments, via the sulfur participation, the 2′,3′-diethylthiolate-ribo derivative 23. Deblocking of 23 with methanolic ammonia afforded the free nuclaoside 24.

Full text of DOI:10.1080/10426500307902

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Phosphorus, Sulfur, and Silicon and the Related
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Some 2′-Modified 4′-Thionucleosides via Sulfur
Participation and Synthesis of Thio-Azt from 4′-
Thiofuranoid 1,2-Glycal
Najim A. Al-Masoudi a , Yaseen A. Al-Soud b & Ahmed I. Khodair c
a Universität Konstanz , Konstanz, Germany
b University of Al al-Bayt , Al-Mafraq, Jordan
c Tanta University (Kafr-El-Sheikh) , Tanta, Egypt
Published online: 27 Oct 2010.
To cite this article: Najim A. Al-Masoudi , Yaseen A. Al-Soud & Ahmed I. Khodair (2003) Some 2′-Modified 4′-Thionucleosides
via Sulfur Participation and Synthesis of Thio-Azt from 4′-Thiofuranoid 1,2-Glycal, Phosphorus, Sulfur, and Silicon and the
Related Elements, 178:6, 1199-1209, DOI: 10.1080/10426500307902
To link to this article: http://dx.doi.org/10.1080/10426500307902
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Phosphorus, Sulfur, and Silicon, 178:1199–1209, 2003
C
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390200477
SOME 20-MODIFIED 40-THIONUCLEOSIDES VIA
SULFUR PARTICIPATION AND SYNTHESIS OF
THIO-AZT FROM 40-THIOFURANOID 1,2-GLYCAL
Najim A. Al-Masoudi,a Yaseen A. Al-Soud,b
and Ahmed I. Khodairc
Universita¨t Konstanz, Konstanz, Germany;a University of Al
al-Bayt, Al-Mafraq, Jordan;b and Tanta University
(Kafr-El-Sheikh), Tanta, Egyptc
(Received September 20, 2002; accepted October 31, 2002)
ThioAZT 14 was synthesized in eight steps from D-arabinose derivative
4 via the new thiofuranoid 1,2-glycal, 5-O-Acetyl-1,2,4-trideoxy-1,4-
epithio-3-O-p-toluenesulfonyl-D-threo-pent-1-enitol (8). Ribosylation
of the thiosugar 6 with thymine afforded regioselectively the nucleo-
side 16. Treatment of 16 with sodium azide in hot DMF gave, after
spontaneous intramolecular displacment, the 20-azido-xylo derivative
18, which furnished the free nucleoside 19 on treatment with methano-
lic ammonia. Similarly, treatment of 16 with sodium ethylthiolate in
boiling methanol led to inversion in configuration and gave, after sev-
eral intramolecular displacments, via the sulfur participation, the 20,30-
diethylthiolate-ribo derivative 23. Deblocking of 23 with methanolic
ammonia afforded the free nuclaoside 24.
Keywords: Antiviral agents; ribosylation; sulfur paricipation; thioAZT;
40-thiofuraniod glycal
There has been increasing interest in recent years in the synthesis
of nucleosides from sugar precursors in which the furanose ring atom
is replaced by a sulfur atom and led to promising antiviral or antitu-
mor nucleosides, such as 40-thiothymidine (1), 40-thio-20deoxyxytidine
(2),1 and 40-thioangustmycin C (3).2 This interest has stimulated
the synthesis of this class of nucleosides, especially those modified at
We thank Miss A. Frieml and Mr. Ha¨gele for the NMR experiments and the mass
spectra measurements, respectively.
Address correspondence to N. A. Al-Masoudi, Fakulta¨t fu¨r Chemie, Universita¨t
Konstanz, Postfach 5560, Konstanz, D-78457 Germany. E-mail: Najim.Al-Masoudi@uni-
konstanz.de
1199

1200
N. A. Al-Masoudi et al.
7
the sugar moiety.3 30-Azido-30-deoxy-thymidine 15 (AZT)8,9 is the
most widely used drug against infection by human immunodeficiency
virus type 1 (HIV-1). Much interest is being shown in the synthe-
sis of the thio analogue 14 with potentially higher activity and lower
toxicity.8,10,11 Recently, the 40-thio analogue 14 has been synthesized by
many laboratories12 via different routes. We now report an alternative
synthesis of 14 via the new thiofuranoid glycal 8, a potentially useful
intermediate for the synthesis of other deoxynucleoside analogues and
in anomeric selective nucleoside synthesis.13 Recently, some examples
of synthesis of protected 4-thio-1,2-glycals were described via different
methods.14,15
RESULTS AND DISCUSSION
Potassium thioacetate reacted selectively with the readily avalaible
tritosylate 416 to give the crystalline xylo thioacetate 5 (51%). The
thioacetyl group (SAc) in 5 was identified from the IR spectrum (
max
1
1695 cm 1), since the structure of 5 was identified from the H NMR
spectrum. The H-1 appeared as a doublet at 4.98 with J1,2 = 3.2 Hz,
indicating the -anomer, while the large coupling (J2,3 = J3,4 = 10.0 Hz),
was evidance for the xylo-configuration. Acetolysis of 5 with a mix-
ture of acetic anhydride, acetic acid and sulfuric acid gave, after
chromatography, the 1,5-di-O-acetyl-2,3-di-O-p-toluenesulfonyl-4-thio-
D-xylofuranose (6) as a syrupy mixture of the and anomers (18%).
The low yield of the recyclized product 6 arose from the fact that many
products can be formed during this reaction due to the presence of the
sulfur atom and the good leaving sulfonate groups. It is well known
that 4-thioxylose and its adenine nucleoside was first prepared by Reist
et al.17 from the ring contraction of methyl 2,3-dibenzoyl-4-S-4-thio- -
D-xylopyranoside and recently was prepared by Marshal et al.18 Ob-
viously, the ring contraction to the furanose 6 occured in the similar
manner to that observed by Reist et al. as well as in the 4-thioribose
series.19 The structure of 6 ( -anomer) was confirmed from the 1H NMR

Some 20-Modified 40-Thionucleosides
1201
spectrum which showed H-1 as a doublet at 6.17 with J1,2 = 3.0 Hz,
while the other J values (J2,3 = 1.5 Hz, J3,4 = 2.7 Hz) are typical for the
xylo-configuration. Treatment of 6 with hydrogen bromide in the pres-
ence of acetic acid at 20 C gave the unstable bromo compound 7 which
was converted directly into the furanoid thioglycal 8 (oil, 30%) by the
action of zinc dust in acetic acid at 80 C. The glycal 8 is stable enough
under nitrogen at 5 C to be purified by chromatography. The structure
1
of glycal was characterized from the H NMR and mass spectra. The
anomeric proton and H-2 appeared as doublet and doublet of doublets
at 6.43 (J1,2 = 3.5 Hz) and 5.67 (J2,3 = 6.7 Hz), respectively, which are
in agreement with the results obtained by Miller et al.14a The H-3 ap-
peared as a doublet of doublets with J = 5.7 Hz, which is indication of the
thereo-configuration. Addition of sodium acetate and p-toluenesulfonic
acid at 20 C to the thioglycal 8 furnished the 2-deoxy-4-thiofuranose
diacetate 9 as an anomeric mixture (50%). The 1H-NMR spectrum of 9
revealed the anomer ratio ( : ) to be about 2:1, since H-1 ( -anomer,
from an HMBC experiment) appeared as a doublet of doublets at 6.20
(J1,2a = 5.6 Hz; J1,2b = 2.7 Hz) and similarly for H-1 ( -anomer) at 6.31
(J1,2a = 5.6 Hz, J1,2b = 1.6 Hz). The H-3 was characterized as a doublet
of doublet of doublets at 4.90 with J values (6.3 Hz, 5.4 Hz, and dif-
ficult to measure J2,3 since H-2 is a multiplet) which suggested the
thereo-configuration of 9 . Both elimination and substitution occurred
when 9 was heated with lithium azide in DMF to give the olefin 10 (oil,
35%) as well as the desired azide 11 (oil, 48%). The structure of 11 ( , -
1
mixture) was elucidated from the H NMR and mass spectra, which
showed close resemblance to the authentic sample prepared by Villa et
al.20 Condensation of 11 with the silylated thymine 12, by applying the
modified Vorbru¨ggen method,21,22 afforded, after purification by chro-
matography, the acetylated nucleoside 13 as an amorphous solid (36%,
, mixture). Deacetylation of 13 with methanolic ammonia gave, after
chromatographic purification (Et2O-Me2CO 99.5:0.5) and precipitation
from ethyl acetate-hexane, the 30azido-30-deoxy-40-thymidine (ThioAZT)
(14) (m.p. 121–123 C, Lit.20 122–123 C) in 21% yield (Scheme 1). The
-configuration of 14 was confirmed by NOE experiment.23 Thus, ir-
radiation of the H-10signal led to enhancement of the signal for H-40
(2.9%) and irradiation of the H-6 signal resulted in the enhancement of
the signals for H-30 (3.0%) an H-50,500 (1.2%).
We next prepared the 40-thioxylonucleoside 16 (67%) from ribosy-
lation of the silylated thymine 12 with the sugar precursor 6, by ap-
plyling Vorbru¨ggen method,21,22 using TMSTfS as catalyst and dry
1
1,2-dichloroethane as solvent at 23 C. The H NMR spectrum of 16
showed a doublet at 6.29, assigned to H-10 with J1,2 = 3.3 Hz, which
suggested the -configuration. The two doublets of doublets at 5.00

1202
N. A. Al-Masoudi et al.
SCHEME 1 Reagents and conditions: (i) KSAc, DMF, 100 C, 72 h; (ii) Ac2O,
HOAc, H2SO4, 0 C; (iii) HBr, HOAc, 20 C, 15 h; (iv) Zn, HOAc, 80 C, 4 h;
(v) NaOAc, TSA, 20 C, 10 h; (vi) LiN3, DMF, 100 C, 5 h; (vii) (12), TMSTfS,
ClCH2CH2Cl, reflux C, 4 h; (viii) NH3, MeOH, 5 C, 15 h.
(J3,4 = 3.0 Hz,) and 4.87 (J2,3 = 1.7 Hz) were attributed to H-30 and
H-20 respectively. These J values give an stereochemical proof of the
xylo-configuration.
The action of nucleophile reagents on compound 16 was investigated.
Thus, treatment of 16 with excess of a 1.5:1.0 mixture of sodium azide
and ammonium chloride in DMF at 120 C for 2 h gave a syrupy mixture
18. Deblocking of the syrup 18 with 16% methanolic ammonia resulted,
after chromatographic purification, in the formation of a foam solid, ten-
tatively identified as 19. The IR spectrum of 19 was charactereized by
1
the absorbtion at 2100 cm 1, and assigned to the azide group. The H
NMR spectrum of 19 demonstrated H-10 as a doublet at 6.19 with
J1 ,2 = 5.5 Hz which is a typical for the -configuration. The H-20 and
0
0
H-30 appeared at 3.98 (J2 ,3 = 1.7 Hz); and 4.37 (J3 ,4 = 4.0 Hz), and
these J values supported the xylo-configuration. These results might
be explained in terms of the intramolecular displacement with the
0
0
0
0

Some 20-Modified 40-Thionucleosides
1203
SCHEME 2 Reagents and conditions: (i) (12); TMSTfS, 78–23 C, 4 h; (ii)
NaN3, NH4Cl, DMF, 120 C, 4 h; (iii) 16% NH3/MeOH, 23 C, 16 h; (iv) NaSEt,
MeOH, reflux, 4 h.
sulfonate group at C-20, via sulfur participation, and led to the interme-
diate 17 which was spontaneously attacked by the azide ion at C-20 to
give, with the retention in configuration, the 20-azido-xylo derivative 18
(Scheme 2). These findings are in accordance with the results obtained
by Miller et al.14a
Treatment of 16 with sodium ethylthiolate in refluxing methanol for
5 h might proceeded similarly as in the previous mechanism by the
intramolecular displacement to give the episulfonium ion 17 which,
attacked by the thiolate ion at C-20, could give, with the retention of
configuration, the unseparable 2-ethylthiolate nucleoside 20. The lat-
ter compound might suffer another displacement via sulfur participa-
tion with the sulfonate group at C-30 to give the episulfonium ion 21
which and again would be attacked by the amido group at C-2 giving
the unseparable 2,20-anhydro derivative 22. The presence of excess of
sodium ethylthiolate in refluxing methanol might lead to the opening
of the anhydro ring at 22 and result in inversion of configuraton and
formation of the syrupy ribo compound 23. Deblocking of 23 afforded
the free nucleoside 24 (38%) as a crystalline compound (Scheme 2). The
structure of 24 was elucidated by spectral analysis (Scheme 2). The
1
H-20 and H-30 signals appeared in the H NMR spectrum as two dou-
0
0
0
0
blet of doublets at 3.98 and 4.37 with J2 ,3 = 3.0 Hz and J3 ,4 = 4.0 Hz

1204
N. A. Al-Masoudi et al.
respectively. These values are an indication of the ribo configuration and
again are in agreement with those of the previously reported xylo and
ribo derivatives.24 More evidence for the formation of 23 is concluded
from the NOE irradiation experiment of the H-10 signal, which led to
enhancement of the signal for H-40 (2.8%) and irradiation of the H-6 sig-
nal which resulted in the enhancement of the signals for H-30 (2.9%).
The HMQC spectrum of 24 showed a 3 JC,H correlation between C-50 and
H-30, as additional evidence for the endo-H-30 (the ribo-configuration).
EXPERIMENTAL
General Procedure
Melting points are uncorrected. 1H NMR spectra were recorded on AC
250 and 600 MHz spectrometers [13C NMR (62.9 MHz)] using tetram-
ethylsilane (TMS) as internal standard with : chemical shift in ppm,
and coupling constants in Hz. Mass were measured in glycerol as matrix
and some ions were measured with sodium ions.
Methyl 4-S-acetyl-4-deoxy-2,3-di-O-p-toluenesulfonyl- -D-xy-
lopyranoside (5). A solution of 4 (4.0 g, 6.38 mmol) in DMF (35 ml) was
stirred under nitrogen with potassium thioacetate (1.0 g, 8.76 mmol) at
117 C for 24 h. After cooling, the brown solution was evaporated to dry-
ness, and the residue was partitioned between CHCl3 (3 50 ml) and
water (50 ml). The combined organic extract was dried (Na2SO4), fil-
tered, and evaporated to dryness. The residue was dissolved in toluene
(5 ml) and poured onto a column of SiO2 (100 g) and eluted, in gradient,
with ethyl acetate (0–10%) and toluene to give 5 (1.78 g, 51%) as a crys-
talline product, m.p. 145–147 C. max 1695 (-SAc), 1740 cm 1(-OAc). 1H
NMR (CDCl3): 7.79–7.45 (m, 8H, Ar); 5.05 (dd, 1H, J3,4 = 10.0 Hz,
H-3); 4.98 (d, 1H, J1,2 = 3.2 Hz, H-1); 4.70 (dd, 1H, J2,3 = 10.0 Hz, H-
2); 4.22 (m, 1H, H-4); 4.09 (dd, 1H, J4,5b = 2.3 Hz, H-5b); 3.60 (dd, 1H,
J5a,5b = 12.5 Hz, H-5a); 3.37 (s, 3H, OMe); 2.47 (s, 3H, C6H4Me); 2.35 (s,
3H, SAc); 2.27 (s, 3H, C6H4Me); 2.08, 1.97 (2s, 6H, 2 OAc). Anal. calc.
for C22H26S3O10 (546.6): C, 48.34; H, 4.79. Found: C, 48.21; H, 4.68. MS:
m/z (FAB) 547 (MH+).
1,5-Di-O-acetyl-2,3-di-O-p-toluenesulfonyl-4-thio-D-xylofura-
nose (6). To a cooled ( 15 C), stirred solution of 5 (2.0 g, 3.66 mmol)
in a mixture of acetic anhydride (25 ml) and acetic acid (25 ml) was
added conc. sulfuric acid (1.5 ml) dropwise. The solution was left at
23 C for 2 days, then mixed with anhydrous sodium acetate (8.0 g)
and evaporated to dryness below 25 C. The residue was partitioned
between chloroform (50 ml) and water (50 ml), and the organic layer
was washed with aqueous solution of sodium bicabonate (50 ml) and

Some 20-Modified 40-Thionucleosides
1205
finally with water (50 ml). The organic extract was decolourized by
warming with charcoal in methanol and then evaporated to dryness.
The residue was dissolved in toluene and poured onto acolumn of SiO2
(50 g). Elution, in gradient, with ethyl acetate (0–10%) and toluene
1
afforded 3 ( , -anomeric mixture 3:1) (0.37 g, 18%) as oil. H NMR
(CDCl3) ( -anomer): 7.81-7.43 (m, 8H, Ar); 6.19 (d, 1H, J1,2 = 3.0 Hz,
H-1); 5.09 (dd, 1H, J3,4 = 2.7 Hz, H-3); 4.85 (dd, 1H, J2,3 = 1.5 Hz; H-2);
4.80 (dd, 1H, J5a,5b = 11.5 Hz, H-5b); 4.54 (dd, 1H, J4,5a = 4.7 Hz, H-5a);
4.19 (m, 1H, J4,5b = 3.7 Hz, H-4); 2.46 (s, 3H, C6H4Me); 2.42 (s, 3H,
C6H4Me); 2.00, 1.90 (2s, 6H, 2 OAc). MS: m/z (FAB) (C23H26S3O10)
581 (MNa+).
5-O-Acetyl-1-bromo-2,3-di-O-p-toluenesulfonyl-4-thio-D-xylo-
furanose (7). A solution of 6 (1.94 g, 3.48 mmol) in a mixture of
HBr/acetic acid solution (30 ml) was stirred at 20 C for 15 h. The
solution was evaporated under high vaccum below 23 C to dryness.
The residue was partitioned between water (50 ml) and chloroform
(2 50 ml), and the combined organic extracts was dried (Na2SO4),
filtered, and evaporated below 23 C to dryness to give 6 (1.15 g,
57%) as oil, which used directly for the next step. MS: m/z (FAB)
(C21H26BrS3O8) 601/603 (MNa+).
5-O-Acetyl-1,2,4-trideoxy-1,4-epithio-3-O-p-toluenesulfonyl-D-
threopent-1-enitol (8). A solution of 7 (1.0 g, 1.72 mmol) in acetic acid
(10 ml) was treated with zinc dust (2.0 g) and stirred at 80 C for 4 h.
After cooling, chloroform (50 ml) was added and washed successively
with water (30 ml), dil. hydrochloric acid (30 ml), an aqueous solution
of sodium bicabonate (30 ml), and finally with water (30 ml). The
organic extract was dried (Na2SO4), filtered, and dried to dryness.
The residue was purified by flash chromatography using toluene-ether
1
(9:1) to give the desired glycal 5 (0.20 g, 35%) as a pure (TLC) oil. H
NMR (CDCl3): 7.69, 7.58 (2d, 4H, Ar); 6.43 (d, 1H, J1,2 = 3.5 Hz, H-1);
5.67 (dd, 1H, J2,3 = 6.7 Hz; H-2); 5.10 (dd, 1H, J3,4 = 5.7 Hz, H-3); 4.88
(dd, 1H, J4,5b = 6.7 H, H-5b); 4.64 (dd, 1H, J5a,5b = 11.3 Hz, H-5b); 4.19
(m, 1H, H-4); 2.43 (s, 3H, C6H4Me); 2.01 (s, 3H, OAc). MS: m/z (FAB)
(C14H16S2O5) 351 (MNa+).
1,5-Di-O-acetyl-2-deoxy-4-thio-3-O-p-toluenesulfonyl-D-threo-
pentofuranose (9). A solution of 8 (0.70 g, 2.13 mmol) in ace-
tonitrile (30 ml) containing sodium acetate (0.41 g, 5.0 mmol) and
p-toluenesulfonic acid (0.17 g, 1.0 mmol) was stirred at 20 C for
10 h. Chloroform (50 ml) was added, and the reaction mixture was
extracted with aqueous solution of sodium bicarbonate (3
30 ml).
The organic layer was dried (Na2SO4), filtered, and evaporated to
dryness. The residue was chromatographed on a SiO2 column (40 g)
using hexane-ether (1:1) as eluent to give 6 (mixture of stereoisomers)

1206
N. A. Al-Masoudi et al.
(0.41, 50%) as a syrup.1H NMR (CDCl3): 7.52, 7.42 (2d, 4H, Ar); 6.26
(dd, 0.4 H, J = 5.5, 1.6 Hz, H-1); 6.22 (dd, 0.6 H, J = 5.4, 2.0 Hz; H-1);
5.09 (dt, 0.6 H, J = 7.6, 5.9 Hz, H-3); 4.90 (ddd, 0.4 H, J 6.3, 5.4 Hz,
H-3); 4.59 (m, 1H, J4,5b = 5.5 Hz, J5a,5b = 11.0 Hz, H-5b); 4.42 (m, 1H,
J4,5a = 8.3 Hz, H-5a); 4.09 (m, 1H, H-4); 2.65–2.55 (m, 2H, H-2a, H-2b);
2.02, 2.40 (s, 3H, C6H4Me); 2.01, 1.98 (2s, 6H, 2 OAc). MS: m/z (FAB)
(C16H20S2O7) 411 (MNa+).
1,5-Di-O-acetyl-3-azido-2,3-deoxy-4-thio- , -D-erythro-pento-
furanose (11). A solution of 9 (1.2 g, 3.1 mmol) in DMF (30 ml) was
treated with lithium azide (0.40 g, 15.4 mmol) with stirring under
nitrogen at 100 C for 5 h. After cooling, the solvent was evaporated
to dryness, and the residue was taken in chloroform (3 30 ml) and
partitioned with water (40 ml). The combined organic extract was
dried (Na2SO4), filtered, and evaporated to dryness. The residue was
chromatographed on a SiO2 (50 g) and eluted, in gradient, with ether
(0–50%) and hexane to give two components. The first eluted compo-
nent (0.23 g, 35%), as an oil, was tentatively identified as the olefin
10 (MS: m/z (FAB) (C9H12SO4) 217 (MH+). The second fraction(0.37 g,
48%), as a pale yellow syrup, was identified as the anomeric mixture
1
of 11 ( : ratio 1:1). The H NMR spectrum (CDCl3) of the mixture
showed close similarity to those anomers obtained by Villa et al.20MS:
m/z (FAB) (C9H13N3SO4) 260 (MH+). The mixture was used directly
for ribosylation without separation
30-Azido-30-deoxy-40-thiothymidine (14 ) and the correspond-
ing -anomer (14 ). A suspension of thymine (200 mg, 1.60 mmol)
in hexamethyldisilazane (10 ml) containing few crystals of ammonium
sulfate was heated under reflux for 5 h. After cooling, the solution was
evaporated to dryness, and the residue was dissolved in anhydrous
acetonitrile (10 ml). To the clear solution, was added compound 11
(207 mg, 1.60 mmol) in anhydrous acetonitrile (10 ml) and trimethylsilyl
trifluoromethanesulfonate (TMSTfS) (290 l) the mixture of which was
then heated under refulx for 4 h. After cooling, the reaction mixture
was diluted with dichloromethane (15 ml) and stirred with saturated
aqueous solution of sodium bicarbonate (30 ml) for 30 min. The organic
layer was dried, filtered, and evaporated to dryness. The residue was
stirred at 23 C with 16% methanolic ammonia solution for 15 h and
then evaporated to dryness. The residue was separated on a column
of SiO2 (5.0 g) using (ether-aceton 99:0.5) as eluent. The first fraction
was assigned to 14 (65 mg, 16%) as a syrup. The 1H NMR (DMSO-d6)
spectrum was identical to that of the sample prepard by Villa et al.20
The second eluted fraction was identified as compound 14 (89 mg,
22%); m.p. 120–123 C (from EtOAc-hexane) (Lit.18 m.p. 122–123 C). 1H
NMR (DMSO-d6): 11.31 (br s, 1H, NH), 7.83 (d, 1H, J 1.0 Hz, H-6);

Some 20-Modified 40-Thionucleosides
1207
6.15 (t, 1H, J1 ,2 a = 7.1 Hz, J1,2b = 7.6 Hz, H-10); 4.50 (q, 1H, H-30); 3.64
0
0
(m, 2H, H-50a, H-50b); 3.37 (q, 1H, H-4); 2.45 (m, 1H, J2 b,3 = 5.0 Hz,
0
0
H-20b); 2.30 (m, 1H, J2 a,3 = 5.0 Hz, J2 a,2 b = 13.5 Hz, H-2a0); 1.81 (d,
3H, Me). 13C NMR (163.3 (C-4), 150.6 (C-6); 109.8 (C-5); 64.2 (C-10);
63.0 (C-50); 59.5 (C-40); 55.2 (C-30); 38.0 (C-20); 12.3 (Me). Anal. calc. for
C10H13N3SO3 (255.3): C, 47.05; H, 5.13. Found: 46.92; H, 5.04. MS: m/s
(FAB) 256 (MH+).
0
0
0
0
1-(5-O-Acetyl-2,3-di-O-p-toluenesulfonyl-4-thio- -D-xylofura-
nosyl)thymine (16). A solution of 6 (500 mg, 0.89 mmol) in dry
1,2-dichloroethane (15 ml) was added to a solution of silylated thymine
[prepared by refluxing thymine (200 mg, 1.59 mmol) and hexam-
ethyldisilzane (HMDS, 15 ml) for 5 h and concentrating the mixture
to a gum] in dry 1,2-dichloroethane (15 ml). During the stirring at
23 C, trimethylsilyl triflouromethylsulfonate (TMSTfS) (150 l) was
added dropwise, and the solution was continued with stirring at
the same temperature for 5 h. The mixture was then diluted with
dichloromethane (30 ml) and then partitioned with saturated aqueous
solution of sodium bicarbonate (3 30 ml). The organic extract was
dried, filtered, and evaporated to dryness. The residue was purified
on a column of SiO2 (20 g), using, in gradient, methanol (0–2%) and
dichloromethane as eluents to give 16 (0.36 g, 67%) as a crystalline
1
product, m.p. 130–134 C. H NMR (CDCl3): 7.91 (d, 1H, J 1.1 Hz,
H-6); 7.75–7.40 (m, 8H, Ar); 6.29 (d, 1H, J1,2 = 3.3 Hz, H-1); 5.00 (dd,
1H, J3,4 = 3.0 Hz, H-3); 4.87 (dd, 1H, J2,3 = 1.7 Hz; H-2); 4.76 (dd, 1H,
J5a,5b = 11.1 Hz, H-5b); 4.53 (dd, 1H, J4,5a = 4.5 Hz, H-5a); 4.18 (m, 1H,
J4,5b = 3.7 Hz, H-4); 2.47 (s, 3H, C6H4Me); 2.40 (s, 3H, C6H4Me); 2.01,
1.92 (2s, 6H, 2 OAc). Anal. calc. for C26H28N2S3O10(624.7): C, 49.99;
H, 4.52; N, 4.48. Found: 49.73; H, 4.44; N, 4.26. MS: m/z (FAB) 625
(MH+).
Reaction of 16 with azide ion. A solution of 16 (250 mg,
0.40 mmol), sodium azide (160 mg, 2.40 mmol), and ammonium chlo-
ride (86 mg, 1.60 mmol) in DMF (15 ml) was stirred at 120 C. After
2 h, additional sodium azide (76 mg, 1.17 mmol) and ammonium chlo-
ride (44 mg, 0.82 mmol) were added, and the reaction was continued
for another 3 h at the same temperature. The micture was cooled to
23 C, the salts were filtered off, and the filtrate was evaporated to a
syrupy mixture. A solution of 16% methanolic ammonia (10 ml) was
added to the syrup, and the solution was stirred at 23 C for 16 h. The
solution was evaporated to dryness, and the residue was partitioned be-
tween water (15 ml) and ether (3 15 ml). The aqueous layer was evap-
orated to dryness, and the residue was co-evaporated to dryness. The
residue was chromatographed on a SiO2 column (15 g) with methanol, in
gradient (0–10%), and chloroform as eluents to give a foam, tentatively

1208
N. A. Al-Masoudi et al.
characterized as (1-(2-azido-2-deoxy-4-thio- -D-xylofuranosyl)thymine
(19). Crystallization from ethanol-petrolium ether gave 48 mg of 16
(40%), m.p. 96–99 C. 1H NMR (CD3OD): 7.93 (d, 1H, J 1.0, H-6); 6.19 (d,
0
0
0
0
0
0
1H, J1 ,2 = 5.5 Hz, H-1 ); 4.80 (br s, 2H, 2 OH); 4.37 (dd, 1H, J3 ,4 = 4.0
Hz, H-30); 3.98 (dd, J2 ,3 = 1.7 Hz, H-2 ); 3.68 (m, 2H, H-5a ,H-5 b); 3.43
(m, 1H, H-40); 1.83 (d, 3H, Me). Anal. calc. for C10H13N5SO4(299.3): C,
40.13; H, 4.38; N, 23.40. Found: 39.82.; H, 4.30; N, 22.98. MS: m/s (FAB)
322 (MNa+).
0
0
0
0
Reaction of 16 with ethylthiolate ion. A solution of 16 (250 mg,
0.40 mmol) in dry methanol (10 ml) containing sodium ethylthiolate (45
mg, 0.50 mmol) was boiled for 5 h. After cooling, the solvent was evapo-
rated to dryness, and the residue was worked up as in the previous ex-
periment after treatment with 16% methanolic ammonia (10 ml) to give
a syrup (120 mg). The syrupy product was chromatographed on a SiO2
column (15 g), using, in gradient, methanol (0–0.5%), and chloroform
as eluents to give a pure foamy solid tentatively identified as 1-(2,3-
dideoxy-2,3-S,S-diethyl-4-thio- -D-ribofuranosyl)thymine (24). (55 mg,
1
38%); m.p. 79-85 C. H NMR (CD3OD): 7.87 (d, 1H, J 1.1 Hz, H-6);
0
0
0
6.59 (d, 1H, J1 ,2 = 5.2 Hz, H-1 ); 4.76 (t, 1H, J = 5.2 Hz, OH); 4.37
0
0
0
0
0
0
(dd, 1H, J3 ,4 = 4.0 Hz, H-3 ); 3.98 (dd, J2 ,3 = 3.0 Hz, H-2 ); 3.68 (m,
2H, H-5a0, H-50b); 3.43 (m, 1H, H-40); 2.75, 2.72 (2q, 4H, J 6.8 Hz,
2
SCH2CH3); 1.83 (d, 3H, Me); 1.37, 1.35 (2t, 6H, 2 SCH2CH3). Anal.
calc. for C14H22N2S3O3(362.5): C, 46.38; H, 6.12; N, 7.73. Found: 46.02.;
H, 6.01; N, 7.53. MS: m/z (FAB) 385 (MNa+).
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