Synthesis and reactions of new 3′-deoxy-5′-thioalkyl-β-D- erythropentofuranosylthymines and related analogues

Article abstract of DOI:10.1080/718990492

5′-Thioalkyl derivatives 4-6 were prepared from direct displacement of the 5′-O-tosylate analogue 3 in moderate yields. Oxidation of 4 and 5 with 1.0 aq. MMMP gave the sulfones 7 and 8, respectively, while similar treatment with 0.5 eq. MMPP or soudium pe

Full text of DOI:10.1080/718990492

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis and Reactions of New 3′-Deoxy-5′-
thioalkyl-β-D-erythro-pentofuranosylthymines and
Related Analogues
Najim A. Al-Masoudi a & Yaseen A. Al-Soud b
a Universität Konstanz, Konstanz, Germany
b University of Al al-Bayt, Al-Mafraq, Jordan
Published online: 18 Jun 2010.
To cite this article: Najim A. Al-Masoudi & Yaseen A. Al-Soud (2003) Synthesis and Reactions of New 3′-Deoxy-5′-thioalkyl-β-
D-erythro-pentofuranosylthymines and Related Analogues, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:12,
2551-2561, DOI: 10.1080/718990492
To link to this article: http://dx.doi.org/10.1080/718990492
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Phosphorus, Sulfur, and Silicon, 178:2551–2561, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390248051
SYNTHESIS AND REACTIONS OF NEW
3ꢀ-DEOXY-5ꢀ-THIOALKYL-β-D-ERYTHRO-
PENTOFURANOSYLTHYMINES AND
RELATED ANALOGUES
Najim A. Al-Masoudia and Yaseen A. Al-Soudb
Universita¨t Konstanz, Konstanz, Germanya and University of
Al al-Bayt, Al-Mafraq, Jordanb
(Received June 9, 2003; accepted July 1, 2003)
5 ꢁ-Thioalkyl derivatives 4–6 were prepared from direct displacement
of the 5 ꢁ-O-tosylate analogue 3 in moderate yields. Oxidation of 4 and
5 with 1.0 aq. MMMP gave the sulfones 7 and 8, respectively, while
similar treatment with 0.5 eq. MMPP or soudium periodate, 4 afforded
the sulfoxide 9. Treatment of 4 and 5 with diphenyl sulphite furnished
the 2,2 ꢁ anhydro analogues 10 and 11, which gave the 2 ꢁ-ethylsulfanyl
derivetives 12 and 13 on treatment with sodium ethanethiolate, re-
spectively. Similarly, 10 gave the 2 ꢁ-azido derivative 14. Compound 17
might obtained from 13, via the episulphonium ion 16. Basic hydrolysis
of 10 furnished the arabino analogue 15.
Keywords: 3ꢁ-Deoxythymines; antitumor agents; sulfones and sulfox-
ide; sulfur participation; thioalkylation
Nucleosides antimetabolites play an important role in the field of
chemotherapy for cancer and viral diseases1 because of their ability to
interefere with DNA synthesis by inhibiting DNA polymerase.2 Chem-
ical modification of the sugar moiety in such nucleosides recently have
received considerable attention.3−8 Since the discovery of Cordycepin,9
a naturally-occuring nucleoside antibiotic with antibactrial and antitu-
mor activity,10 its identification as 3ꢁ-deoxyadenosine11 has increased
in recent years along with interest in the chemistry and biology of
3ꢁ-deoxynucleosides in general. A number of related nuleoside ana-
logues have been prepared.12−14 Breslow et al.15 have investigated the
propreties of 2ꢁ,5ꢁꢁ linked oligomers as well as the synthesis of protected
Address correspondence to N. A. Al-Masoudi, Former Fachbereich Chemie, Univer-
sita¨t Konstanz, Postfach 5560, D-78457 Konstanz, Germany. E-mail: Najim. Al-Masoudi@
gmx.de
2551

2552
N. A. Al-Masoudi and Y. A. Al-Soud
phosphoramidites of 3ꢁ-deoxyadenosine and 3ꢁ-deoxy-5-methyluridine
for use in solid phase oligonucleotide synthesis. On the other hand,
it has been reported that among several 5ꢁ-thioalkyl nucleosides, 5ꢁ-S-
ethyl-5ꢁ-thiothymidine 1 was found to be a noncompetitive inhibitor for
the human tumor cell lines,16,17 the metachondrial, and cytoplasmic
isozymes (% inhibition of rat M-TK and C-TK = 7.0 µM and 4.0 µM,
respectively, in comparison to the thymidine itself 7.2 µM and 2.25 µM,
respectively).16 Recently some 5ꢁ-thioalkyl nucleosides were found
to exhibite activity as antitumor or antiviral agents.18−20 Agrofoglio
et al.21 have reported the anticancer activity of 5ꢁ-S-ethyl 3ꢁ-deoxy-5ꢁ-
thiothymidine with a moderate activity (IC50 = 90.2ꢁ µM). As a part of
our program22−30 on exploring the syntheses and biological evaluation
of new thiosugars and their nucleosides, we report here the synthesis of
3ꢁ-deoxynucleosides carrying modified sugar moieties bearing different
thioalkyl groups and their chemical behavior toward some nucleophiles
as promising anticancer or antiviral candidates.
RESULTS AND DISCUSSION
The starting material 3ꢁ-deoxy-5ꢁ-O-toluene-p-sulphonyl-β-D-erythro-
pentofuranosylthymine (3)23 was prepared in our laboratory in 45%
from tosylation of the previously reported free nucleoside 2.15 Reac-
tion of the tosylate 3 with sodium thiophenolate, methyl 3-merca-
ptopropionate, and methyl 3-mercapto-2-oxo-propionate in DMF at
70◦C gave, after chromatographic separation, the 5ꢁ-alkylthiothymine
derivatives 4–6 in 52, 59, 56% yield respectively. The structures of 4–6
were identified from the 1H NMR spectra, which showed common pat-
tern of spectral features. The chemical shifts of H-1ꢁ in compounds 4–6
ꢁ
ꢁ
(δH 5.69, 5.66, and 5.68) with the corresponding J
values (2.0, 2.1,
1 ,2
and 2.4 Hz respectively) clearly indicated that these compounds have
the β-configuration and are in agreement with the N-type confor-
mation of the sugar moiety. The signals at δH 4.60, 4.57, and 4.58,

Furanosylthymines
2553
respectively, as doublet of doublets of doublets were attributed to H-2ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
(J
< 1.0 Hz, J
4.5, 4.4, and 4.2 Hz, respectively) while
2 ,3 (exo)
2 ,3 (endo)
ꢁ
ꢁꢁ
the multiplets at δH 4.38, 4.37, and 4.39, with J
values of 4.6, 4.5,
4 ,5
and 4.5 Hz, respectively, were assigned to H-4ꢁ. The H NMR spectra
1
revealed the typical erythro configuration where H-3ꢁꢁ protons were ap-
ꢁꢁ
ꢁ
peared as doublets of doublets at δH 2.10, 2.08, and 2.11 (J
4.5 Hz),
3 ,4
and H-3ꢁ protons were appeared as doublets of doublets of doublets at δH
ꢁ
ꢁ
1.67, 1.64, and 1.65 (J 10.2, 10.0, and 10.2 Hz, Jgem∼13.5 Hz respec-
3 ,4
tively. Furthermore, the assignments of H-3ꢁ and H-3ꢁꢁ were determined
from the irradiation experiments of H-2ꢁ which revealed a clear decou-
pling with these protons and as a result of this irradiation, the former
protons in 4–6 were enhanced to the doublet of doublets. The thioalkyl
groups at C-5ꢁ were fully analyzed.
Next, we studied the oxidation of 4 and 5 by different methods.
Thus, boiling with 1.0 mmol equivalent of magnesium monoperoxyph-
thalate hexahydrate (MMPP) in CH2Cl2/MeOH, by using the procedure
of Agrofoglio and coworkers,21 resulted in the formation of the sulfone
derivatives 7 (75%), and 8 (69%), respectively. Similarly, oxidation of
4 with 0.50 mmol equivalent under the same condition furnished, af-
ter chromatography, the diastereomeric mixture (R: S) of sulfoxide 9
(70%). Altenatively, 9 was obtained in 65% yield, by following Walker
et al.31 procedure, from treatment of 4 with sodium periodate in aque-
ous MeOH between 0–23◦C for 18 h. The structures of 7–9 was secured
by the 1H NMR and mass spectra [FABMS m/z: 367, 399, 383 (MNa)+
respectively] (Scheme 1).
When the 5ꢁ-thioalkyl derivatives 4 and 5 were heated with a four-
fold excess of diphenyl sulphite, by applying Reese et al.32 procedure,
at 156◦C 1 in dimethylacetamide solution and catalytic amount of
1-methylimidazole then the products treated with triethylamine, it re-
sulted in the formation of the oily 2,2ꢁ-anhydro analogues 10 and 11
respectively. The formation of such anhydro derivatives of thymidine
and uridine and their yield percentages were discussed extensively by
many laboratories using different reagents (references cited by Walker
et al.31). The structures of 10 and 11 were characterized by their spectral
analysis. The H-1ꢁ in the 1H NMR spectra of 10 and 11 were appeared
ꢁ
ꢁ
as doublets at δH 5.97 and 5.96 with J
5.5 Hz and 5.7 Hz, respec-
1 ,2
tively, indicating for the arabino configuration. These data are in con-
sistent with those of the 2,2ꢁ-anhydro-1-[3-deoxy-5-O-(4-methoxytrityl)-
β-D-threopentofuranosyl] thymine, prepared by Lin et al.33
Treatment of 10 with sodioum ethanethiolate in MeOH at 23◦C for
16 h gave, after chromatography, a foamy solid tentatively identified
as 12 (87%). Interestingly, under the above condition, 11 gave two
products, separated by chromatography. The higher running product

2554
N. A. Al-Masoudi and Y. A. Al-Soud
SCHEME 1 Conditions and reagents: (i) PhSNa, HS(CH2)2CO2Me or
NaSCH2COCO2Me/DMF, 70◦C, 3 h; (ii) MMPP, 1.0 eq., CH2Cl2/MeOH, reflux,
3 h; (iii) a) 0.5 eq. MMPP/as in ii, b) 0.50 M NalO4, aq. MeOH, 0–23◦C, 18 h.
1
was assigned from the H NMR and mass spectra [FABMS m/z 441
(MNa)+] and identified as 17 (32%), while the second eluted product
was the major, characterized as 13 (63%) (Scheme 2). Compounds 12,
13, and 17 showed almost a similar pattren of spectra, especially the
thioethyl group which appeared as quartets at δH 2.46, 2.44, and 2.45
for methylenes of SEt group, respectively, meanwhile triplets at δH 1.18,
1.15, and 1.17 were asigned for the ethyl groups, respectively. The sig-
nals at δH 2.67, and 1.27 in 17 were attributed for the methylene and
ethyl groups of the propionate moiety. The formation of 17 might be
explained in terms of the intramolecular displacement of the methoxy
group of 13, via sulfur participation, leading to the episulphonium in-
termediate 16 which was ready for attack by the thiolate ion furnishing
17 as shown in Scheme 2.
Heating of 10 with lithium azide in DMF at 23◦C afforded, after
chromatography, the azide derivative 14 (70%). The appearance of a
strong IR absorption at 2100 cm−1 was atrributed to the azido group.
The structure of 14 was elucidated by the spectral analysis. The H-1ꢁ
signal appeared in the 1H NMR spectrum as a doublet at δH 6.21 (J
ꢁ
ꢁ
1 ,2
2.3 Hz), while H-2ꢁ appeared as doublets of doublet of doublets at δH
ꢁ
ꢁꢁ
ꢁ
ꢁ
4.87 (J2 ,3 (exo) < 1.0 Hz, J2 ,3
4.4 Hz). The doublet and doublet of
(endo)
ꢁꢁ
ꢁ
ꢁ
ꢁ
doublets of doublets at δH 2.09 (J
4.3 Hz) and 1.60 (J
10.4 Hz,
3 ,4
3 ,4
J
gem 13.5 Hz) were assigned to the exo proton H-3ꢁꢁ and the endo-proton

Furanosylthymines
2555
SCHEME 2 Conditions and reagents: (i) diphenyl sulphite, 156◦C, Ac-NMe,
1-Me-imidazole; 1 h, then → 0◦C, Et3N; (ii) EtSNa, MeOH, 23◦C, 16 h; (iii) LiN3,
DMF, 23◦C, 16 h.
H-3ꢁ, respectively. These J values give an stereochemical proof of the
erythro configuration.
Hydrolysis of 10 with 1N NaOH in 50% EtOH at 23◦C, followed by
neutralization with HOAc to pH 7.0 gave the arabino analogue 15 in
83% yield. The structural feature of 15 was depicted from the 1H NMR
ꢁ
ꢁ
and mass spectra. The J
coupling in 15 (7.3 Hz) is in agreement
1 ,2
with the arabino-configuration34 of the glycosidic bond. The anticancer
activity of compounds 4–8 and 12–14 is under investigation.
In conclusion, the electronic mobility, the lipophilic propreties and
molecular distribution of the 2ꢁ-, 5ꢁ-alkylthio and 2ꢁ-azido groups in the
new synthesized compounds have been adjusted to be close to those
biological active substances reported previously and might show signif-
icant anticancer activity.
EXPERIMENTAL
General Procedure
1
Melting points are uncorrected. H NMR spectra were determined at
300 and 600 MHz with TMS as internal standard and on a δ scale in
ppm. 3-Nitrophenol (NBOH) or glycerol were used in the EI and FAB
mass measurements as matrices. Some molecular ions were detected
by doping the sample with Na+ ion.

2556
N. A. Al-Masoudi and Y. A. Al-Soud
General Procedure for Preparation of 5ꢀ-S-Alkyl-5ꢀ-thio
Derivatives of 3ꢀ-Deoxy-β-D-erythro-
pentofuranosylthymine
A solution of 3 (1.00 g, 2.60 mmol) in DMF (15 ml) and the mercapto
precursor (4.00 mmol) was heated at 70◦C, with stirring, for 3 h under
argon atmosphere. After cooling, the solution was evaporated under
vaccum to dryness and the residue was partitioned between CH2Cl2
(3 × 20 ml) and water (20 ml). The combined organic extracts were dried
(Na2SO4), filtered, and evaporated to dryness to give brown product.
This was dissolved in CH2Cl2 (2 ml) and poured onto SiO2 column (20 g)
and eluted, in gradient, with MeOH (0-10%) and CH2Cl2 to give the
desired products.
1-(3-Deoxy-5-S-phenyl-5-thio-β-D-erythropentofuranosyl)thymine (4).
From sodium thiophenolate (0.53 g). Yield: 0.45 g (52%), as a foam.
1H NMR (DMSO-d6/D2O): δ 7.52 (s, 1H, H-6); 7.32–7.19 (m, 3H, Ar);
6.97 (m, 2H, Ar); 5.69 (d, 1H, J1 ,2 = 2.0 Hz, H-1ꢁ); 4.60 (ddd, 1H,
ꢁ
ꢁ
J2 ,3 < 1.0 Hz, J2 ,3 = 4.5 Hz, H-2ꢁ); 4.38 ( m, 1H, J4 ,5 = 4.6 Hz, H-4ꢁ);
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁꢁ
2.79 (dd, 1H, J4 ,5 = 6.5 Hz, H-5ꢁ); 2.69 (dd, 1H, J5 ,5 = 12.0 Hz, H-5ꢁꢁ);
ꢁ
ꢁ
ꢁ
ꢁꢁ
2.10 (dd, 1H, J3 ,4 = 4.5 Hz, H-3ꢁꢁ); 1.92 (s, 3H, C5 Me); 1.67 (ddd, 1H,
ꢁꢁ
ꢁ
J3 ,4 = 10.2 Hz, J3 ,3 = 13.5 Hz, H-3ꢁ). Anal. calcd for C16H18N2O4S
(334.4): C, 57.47; H, 5.43; N, 8.38. Found: C, 57.28; H, 5.35; N, 8.19.
MS: m/z (FAB) 335 (MH)+.
ꢁ
ꢁ
ꢁ
ꢁꢁ
3-(3-Deoxy-β-D-erythrpentofuranosylthymin-5-ylsulfanyl)-propionic
acid methyl ester (5). From methyl 3-mercaptopropionate (0.43 g).
Yield: 0.53 g (59%), m.p. 142-146◦C. 1H NMR (DMSO-d6/D2O): δ 7.50 (s,
1H, H-6); 5.66 (d, 1H, J1 ,2 = 2.1 Hz, H-1ꢁ); 4.57 (ddd, 1H, J2 ,3 < 1.0 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁꢁ
J2 ,3 = 4.4 Hz, H-2 ); 4.37 (m, 1H, J4 ,5 = 4.5 Hz, H-4 ); 3.61 (s, 3H, OMe);
3.12 (t, 2H, J = 6.7 Hz, COCH2); 2.76 (dd, 1H, J4 ,5 = 6.3 Hz, H-5ꢁ); 2.65
ꢁ
ꢁ
(dd, 1H, J5 ,5 = 12.1 Hz, H-5ꢁꢁ); 2.52 (t, 2H, J = 6.7 Hz, SCH2); 2.08
ꢁ
ꢁꢁ
(dd, 1H, J3 ,4 = 4.5 Hz, H-3ꢁꢁ); 1.91 (s, 3H, C5 Me); 1.64 (ddd, 1H, J3 ,4
ꢁꢁ
ꢁ
ꢁ
ꢁ
= 10.0 Hz, J3 ,3 = 13.2 Hz, H-3ꢁ). Anal. calcd for C14H20N2O6S (344.4):
C, 48.83; H, 5.85; N, 8.13. Found: C, 48.66; H, 5.76; N, 8.02. MS: m/z
(FAB) 345 (MH)+.
ꢁ
ꢁꢁ
3-(3-Deoxy-β -D-erythropentofuranosylthymin-5-ylsulfanyl)-2-oxo-
propionic acid methyl ester (6). From methyl 3-mercapto-2-oxo-
1
propionate (0.62 g). Yield: 0.52 g (56%), as a foam. H NMR (DMSO-
ꢁ
ꢁ
d6/D2O): δ 7.50 (s, 1H, H-6); 5.68 (d, 1H, J1 ,2 = 2.4 Hz, 4.58 (ddd, 1H,
J2 ,3 < 1.0 Hz, J2 ,3 = 4.2 Hz, H-2ꢁ); 4.39 (m, 1H, J4 ,5 = 4.4 Hz, H-4ꢁ);
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁꢁ
4.01 (s, 2H, SCH2); 3.70 (s, 3H, OMe); 2.80 (dd, 1H, J4 ,5 = 6.2 Hz, H-5ꢁ);
ꢁ
ꢁ
2.71 (dd, 1H, J5 ,5 = 12.0 Hz, H-5ꢁꢁ); 2.11 (dd, 1H, J3 ,4 = 4.3 Hz, H-3ꢁꢁ);
ꢁ
ꢁꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
1.92 (s, 3H, C5 Me); 1.65 (ddd, 1H, J3 ,4 = 10.2 Hz, J3 ,3 = 13.1 Hz,

Furanosylthymines
2557
H-3ꢁ). Anal. calcd for C14H18N2O7S (358.4): C, 46.92; H, 5.06; N, 7.82.
Found: C, 46.75; H, 7.74; N, 7.73. MS: m/z (FAB) 359 (MH)+.
1-(3-Deoxy-5-S-phenylsulphonyl-5-thio-β-D-erythropentofuranosyl)-
thymine (7). A solution of magnesium monoperoxyphthalate hexahy-
drate (MMPP) (0.30 g, 0.61 mmol, 1.0 eq.) in CH2Cl2 (7 ml) was added
to a solution of 4 (0.20 g, 0.60 mmol) in CH2Cl2/MeOH (9:1, v/v, 10 ml).
The solution was heated under reflux, with stirring, for 3 h. After
cooling, the solution was filtered (hyflo) and evaporated to dryness
at >40◦C. The residue was purified on a SiO2 column (5.00 g) using
CH2Cl2 MeOH (9:1, v/v) as eluent to give 7 (0.16 g, 75%) as a white
1
solid, m.p. 218–221◦C. H NMR (DMSO-d6/D2O): δ 7.53 (d, 1H, J =
1.2 Hz, H-6); 7.39–7.29 (m, 3H, Ar); 7.03 (m, 2H, Ar); 5.70 (d, 1H,
ꢁ
J1 ,2 = 2.1 Hz, H-1 ); 4.63 (ddd, 1H, J2 ,3 < 1.0 Hz, J2 ,3 = 4.3 Hz, H-2ꢁ);
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
4.39 (m, 1H, J4 ,5 = 4.5 Hz, H-4ꢁ); 2.81 (dd, 1H, J4 ,5 = 6.5 Hz, H-5ꢁ);
ꢁ
ꢁꢁ
ꢁ
ꢁ
2.76 (dd, 1H, J5 ,5 = 12.1 Hz, H-5ꢁꢁ); 2.14 (dd, 1H, J3 ,4 = 4.4 Hz, H-3ꢁꢁ);
ꢁ
ꢁꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
1.91 (d, 3H, J = 1.2 Hz, C5 Me); 1.68 (ddd, 1H, J3 ,4 = 10.0 Hz, J3 ,3
=
13.4 Hz, H-3ꢁ). Anal. calcd for C16H18N2O6S (366.4): C, 52.45; H, 4.95;
N, 7.65. Found: C, 52.34; H, 4.86; N, 7.49. MS: m/z (FAB) 367 (MNa)+.
3-(3-Deoxy-β-D-erythropentofuranosylthymin-5-ylsulfonyl)-propio-
nic acid methyl ester (8). From 5 (0.20 g, 0.58 mmol) and magnesium
monoperoxyphthalate (MMPP) (0.29 g, 0.58 mmol, 1.0 eq.) in the
manner described for 7. Yield: .0.15 g (69%) as a white solid, m.p.
1
168–170◦C. H NMR (DMSO-d6/D2O): δ 7.52 (d, 1H, J = 1.2 Hz, H-6);
5.72 (d, 1H, J1 ,2 = 2.0 Hz, H-1ꢁ); 4.61 (ddd, 1H, J2 ,3 < 1.0 Hz, J2 ,3
=
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
4.6 Hz, H-2ꢁ); 4.48 (m, 1H, J4 ,5 = 4.5 Hz, H-4ꢁ); 3.75 (s, 3H, OMe); 3.25
ꢁ
ꢁꢁ
ꢁ
ꢁ
(m, 2H, COCH2); 2.99 (m, 2H, SO2CH2); 2.90 (dd, 1H, J4 ,5 = 6.2 Hz,
H-5ꢁ); 2.80 (dd, 1H, J5 ,5 = 12.0 Hz, H-5ꢁꢁ); 2.10 (dd, 1H, J3 ,4 = 4.5 Hz,
ꢁ
ꢁꢁ
ꢁꢁ
ꢁ
H-3ꢁꢁ); 1.91 (d, 3H, J = 1.2 Hz, C5 Me); 1.66 (ddd, 1H, J3 ,4 = 10.1 Hz,
ꢁ
ꢁ
J3 ,3 = 13.5 Hz, H-3ꢁ). Anal. calcd for C14H20N2O8S (376.4): C, 44.68;
H, 5.36; N, 7.44. Found: C, 44.49; H, 5.28; N, 7.26. MS: m/z (FAB) 399
(MNa)+.
ꢁ
ꢁꢁ
( R)- and ( S)-Sulfoxides of 1-(3-Deoxy-5-S-phenyl-5-thio-β-D-erythro-
pentofuranosyl) thymine (9).
Method A. From 4 (0.20 g, 0.60 mmol) and MMPP (0.15 mg, 0.30 mmol,
0.50 eq.) in the manner described for 7. The product was purified on a
SiO2 column (5.00 g), using CH2Cl2 MeOH 4:1, v/v) as eluent. Yield:
0.15 g, (70%), m.p. 176–179◦C. 1H NMR (DMSO-d6/D2O): δ 7.54 (s, 1H,
ꢁ
ꢁ
H-6); 7.40–7.31 (m, 3H, Ar); 7.03 (m, 2H, Ar); 5.74 (d, 1H, J1 ,2 = 2.0 Hz,
H-1ꢁ); 4.67 (ddd, 1H, J2 ,3 < 1.0 Hz, J2 ,3 = 4.4 Hz, H-2ꢁ); 4.47 (m, 1H,
ꢁ
ꢁ
ꢁ
ꢁꢁ
J4 ,5 = 4.5 Hz, H-4ꢁ); 2.95 (dd, 1H, J4 ,5 = 6.5 Hz, H-5ꢁ); 2.81 (dd, 1H,
ꢁ
ꢁꢁ
ꢁ
ꢁ
J5 ,5 = 12.0 Hz, H-5ꢁꢁ); 2.12 (dd, 1H, J3 ,4 = 4.5 Hz, H-3ꢁꢁ); 1.90 (s, 3H,
ꢁ
ꢁꢁ
ꢁꢁ
ꢁ

2558
N. A. Al-Masoudi and Y. A. Al-Soud
C5 Me); 1.70 (ddd, 1H, J3 ,4 = 10.0 Hz, J3 ,3 = 13.4 Hz, H-3ꢁ). Anal.
calcd for C16H18N2O5S (350.4): C, 54.85; H, 5.18; N, 7.99. Found: C,
54.62; H, 5.02; N, 7.78. MS: m/z (FAB) 351 (MH)+; 373 (MNa)+.
ꢁ
ꢁ
ꢁ
ꢁꢁ
Method B. To a stirred solution of 4 (0.30 g, 0.90 mmol) in water (13 ml)
and MeOH (13 ml) at 0◦C was added a 0.05 M aq. solution of soudium
metaperiodate (35 ml) . The reaction mixture was then left to warm
to room temperature (23◦C) for 18 h, followed by purification of the
product by column chromatography (SiO2, CH2Cl2/MeOH 4:1, v:v) to
afford 9 (0.21 g, 65%). All the physical properties are identical to those
of the authetic sample prepared in method a.
Formation of 2,2ꢁ-anyhro derivatives of 1-(5-S-alkyl-5-thio-3-dexoy-
β-D-threopentofuranosyl)thymines. A mixture of 4 or 5 (1.49 mmol),
diphenyl sulphite (1.39 g, 5.96 mmol), 1-methylimidazole (0.03 ml,
0.31 mmol), and N,N-dimethylacetamide (15 ml) was stirred at 156
1◦C. After 1 h, the products were cooled to 0◦C and then poured, with
stirring, into a cooled (ice-bath) mixture of Et3N (8 ml) and water
(15 ml). After almost 40-45 min, where the temperature raised to 23◦C,
the resulting solution was extracted with CH2Cl2 (4 × 14 ml). The com-
bined organic extracts were dried (Na2SO4), filtered and evaporated to
dryness. The residue was chromatographed on a SiO2 column (10.00 g)
using CH2Cl2 MeOH 9:1, v/v) as eluent to give 10 or 11 as a gumy
product.
2,2ꢁ-Anhydro-1-(3ꢁ-deoxy-5ꢁ-S-phenylsulphonyl-5ꢁ-thio-β-D-threopento-
1
furanosyl)thymine (10). From 4 (0.50 g). Yield: 0.33 g (70%). H NMR
(DMSO-d6): δ 7.52 (s, 1H, H-6); 7.32-7.19 (m, 3H, Ar); 6.97 (m, 2H, Ar);
5.97 (d, 1H, J1 ,2 = 5.5 Hz, H-1ꢁ); 4.98 (m, 1H, H-2ꢁ); 4.38 ( m, 1H, J4 ,5
ꢁ
ꢁ
ꢁ
ꢁꢁ
= 4.6 Hz, H-4ꢁ); 2.79 (dd, 1H, J4 ,5 = 6.5 Hz, H-5ꢁ); 2.69 (dd, 1H, J5 ,5
=
ꢁ
ꢁ
ꢁ
ꢁꢁ
12.0 Hz, H-5ꢁꢁ); 2.10 (m, 1H, H-3ꢁꢁ); 1.92 (s, 3H, C5-Me); 1.67 (m, 1H,
H-3ꢁ). MS (C16H16N2O3S): m/z (FAB) 317 (MH)+; 339 (MNa)+.
3-(2,2ꢁ-Anhydro-3-deoxy-β-D-threopentofuranosylthymin-5-ylsulfonyl)-
propionic acid methyl ester (11). From 5 (0.51 g). Yield: 0.29 g (59%).
1H NMR (DMSO-d6): δ 7.50 (s, 1H, H-6); 5.96 (d, 1H, J1 ,2 = 5.7 Hz,
ꢁ
ꢁ
H-1ꢁ); 4.87 (m, 1H, H-2ꢁ); 4.48 (m, 1H, H-4ꢁ); 3.61 (s, 3H, OMe); 3.14
(t, 2H, J = 6.7 Hz, COCH2); 2.79 (dd, 1H, J4 ,5 = 6.3 Hz, H-5ꢁ); 2.65
ꢁ
ꢁ
(dd, 1H, J5 ,5 = 12.1 Hz, H-5ꢁꢁ); 2.52 (t, 2H, J = 6.7 Hz, SCH2); 2.08 (dd,
ꢁ
ꢁꢁ
1H, J3 ,4 = 4.5 Hz, H-3ꢁꢁ); 1.91 (s, 3H, C5-Me); 1.64 (ddd, 1H, J3 ,4
=
ꢁꢁ
ꢁ
ꢁ
ꢁ
10.0 Hz, J3 ,3 = 13.2 Hz, H-3ꢁ). MS (C14H18N2O5S): m/z (FAB) 327
ꢁ
ꢁꢁ
(MH)+; 349 (MNa)+.
1-(3ꢁ-Deoxy-2ꢁ-S-ethyl-5ꢁ-S-phenyl-2ꢁ,5ꢁ-dithio-β-D-erythropentofura-
nosyl)thymine (12). Ethanethiol (0.37 ml, 5.04 mmol), NaH (60%,
dispersion in mineral oil, 0.06 g, 2.52 mmol) and dry DMF (10 ml) were

Furanosylthymines
2559
stirred together at 23◦C for 5 min. Compound 10 (0.40 g, 1.26 mmol)
was added to the resulting solution, and the reactants were stirred at
23◦C. After 18 h, solid CO2 (0.60 g) was added, and the products were
evaporated (<100◦C) under reduced pressure. The residue was poured
onto SiO2 column using, in gradient, MeOH (0–10%) and CH2Cl2
as eluent to give 12 (0.42 g, 87%) as a pure foamy solid. 1H NMR
(DMSO-d6: δ 10.28 (s, 1H, NH); 8.10 (s, 1H, H-6); 7.34-7.22 (m, 3H,
Ar); 6.96 (m, 2H, Ar); 6.50 (d, 1H, J1 ,2 = 3.5 Hz, H-1ꢁ); 5.19 (ddd, 1H,
ꢁ
ꢁ
J2 ,3 < 1.0 Hz, J2 ,3 = 4.1 Hz, H-2ꢁ); 4.32 (m, 1H, H-4ꢁ); 2.80 (dd, 1H,
ꢁ
ꢁ
ꢁꢁ
ꢁ ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
J4 ,5 = 6.4 Hz, H-5 ); 2.74 (dd, 1H, J5 ,5 = 12.8 Hz, H-5 ); 2.46 (q, 2H, J =
7.4 Hz, SCH2CH3); 2.09 (dd, 1H, J3 ,4 = 4.3 Hz, H-3ꢁꢁ); 1.89 (s, 3H,
ꢁꢁ
ꢁ
C5 Me); 1.60 (ddd, 1H, J3 ,4 = 10.4 Hz, J3 ,3 = 13.5 Hz, H-3ꢁ); 1.18 (t,
3H, SCH2CH3). Anal. calcd for C18H22N2O3S2 (378.5): C, 57.12; H, 5.86;
N, 7.40. Found: C, 56.93; H, 5.78; N, 7.21. MS: m/z (FAB) 379 (MH)+.
ꢁ
ꢁ
ꢁ
ꢁꢁ
3-(3-Deoxy-2-S-ethyl-2,5-dithio-β-D-erythropentofuranosylthymin-5-
ylsulfanyl)-propionic acid methyl ester (13) and 3-(3-deoxy-2-S-ethyl-2,
5-dithio-β-D-erythropentofuranosyl-thymin-5-ylsulfanyl)-propionic acid
thioethyl ester (17). From 11 (0.40 g, 1.22 mmol), NaH (0.06 g,
2.44 mmol) and ethanethiol (0.36 ml, 4.88 mmol) in the manner
described for 12. After working up the reaction mixture, the crude
products were chromatographed on a SiO2 column (10 g), using, in
gradient, MeOH (0–5%) and CH2Cl2 as eluent to give first a foam,
1
tentatively identified as 17 (0.16 g, 32%). H NMR (DMSO-d6): 10.20
(s, 1H, NH); 7.96 (br s, 1H, H-6); 6.42 (d, 1H, J1 ,2 = 2.3 Hz, H-1ꢁ); 4.49
ꢁ
(m, 1H, H-2ꢁ); 4.29 (m, 1H, H-4ꢁ); 3.01 (t, 2H, J = ꢁ6.6 Hz, COCH2); 2.75
(dd, 1H, J4 ,5 = 6.2 Hz, H-5ꢁ); 2.62 (dd, 1H, J5 ,5 = 12.0 Hz, H-5ꢁꢁ); 2.67
(q, 2H, J = 7.1 Hz, COSCH2CH3); 2.50 (t, 2H, J = 6.6 Hz, SCH2); 2.44
ꢁ
ꢁ
ꢁ
ꢁꢁ
(q, 2H, J = 7.2 Hz, SCH2CH3); 1.98 (dd, 1H, J3 ,4 = 4.5 Hz, H-3ꢁꢁ);
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
1.91 (s, 3H, C5 Me); 1.57 (ddd, 1H, J3 ,4 = 10.2 Hz, J3 ,3 = 13.3 Hz,
H-3ꢁ); 1.27 (t, 3H, COSCH2CH3); 1.15 (t, 3H, SCH2CH3). Anal. calcd
for C17H26N2O4S3(418.6): C, 48.78; H, 6.26; N, 6.69. Found: C, 48.52;
H, 6.17; N, 6.39. MS: m/z (FAB) 441 (MNa)+.
Further elution with CH2Cl2 MeOH (93:7, v:v) afforded a foamy
solid, tentatively identified as 13 (0.26 g, 63%). 1H NMR (DMSO-d6): δ
10.23 (s, 1H, NH); 8.06 (s, 1H, H-6); 6.43 (d, 1H, J1 ,2 = 2.3 Hz, H-1ꢁ);
ꢁ
ꢁ
4.50 (m, 1H, H-2ꢁ); 4.37 (m, 1H, H-4ꢁ); 3.60 (s, 3H, OMe); 3.06 (t, 2H,
J = 6.5 Hz, COCH2); 2.79 (dd, 1H, J4 ,5 = 6.0 Hz, H-5ꢁ); 2.67 (dd, 1H,
ꢁ
ꢁ
J5 ,5 = 12.0 Hz, H-5ꢁꢁ); 2.52 (t, 2H, J = 6.5 Hz, SCH2); 2.45 (q, 2H, J =
ꢁ
ꢁꢁ
7.0 Hz, SCH2CH3); 2.02 (dd, 1H, J3 ,4 = 4.4 Hz, H-3ꢁꢁ); 1.89 (s, 3H,
ꢁꢁ
ꢁ
C5 Me); 1.63 (ddd, 1H, J3 ,4 = 10.0 Hz, J3 ,3 = 13.1 Hz, H-3ꢁ); 1.17 (t,
3H, SCH2CH3). Anal. calcd for C16H24N2O5S2(388.5): C, 49.47; H, 6.23;
N, 7.21. Found: C, 49.27; H, 6.14; N, 7.00. MS: m/z (FAB) 389 (MH)+.
ꢁ
ꢁ
ꢁ
ꢁꢁ

2560
N. A. Al-Masoudi and Y. A. Al-Soud
2ꢁ-Azido-2ꢁ,3ꢁ-dideoxy-5ꢁ-S-phenyl-5ꢁ-thio-β-D-erythropentofuranosyl-
thymine (14). A solution of 10 (0.35 g, 1.11 mmol) in N,N-dimethyl-
acetamide (10 ml) and LiN3 (0.10 g, 0.32 mmol) was stirred at 23◦C
for 16 h under nitrogen atmosphere. After cooling the solution was
evaporated to dryness at temperature <40◦C and the residue was
partitioned between water (20 ml) and CH2Cl2 (3 × 15 ml). The
combined organic extracts were dried (Na2SO4), filetered and evapo-
rated and the residue was poured onto short SiO2 column and eluted
CH2Cl2 MeOH (95:5, v/v) to give 12 (0.28 g, 70%)) as a foam. 1H NMR
(DMSO-d6): δ 10.12 (s, 1H, NH); 7.52 (s, 1H, H-6); 7.39–7.29 (m, 3H,
ꢁ
ꢁ
ꢁ
Ar); 7.03 (m, 2H, Ar); 6.21 (d, 1H, J1 ,2 = 2.3 Hz, H-1 ); 4.87 (ddd, 1H,
J2 ,3 < 1.0 Hz, J2 ,3 = 4.4 Hz, H-2ꢁ); 4.27 (m, 1H, J4 ,5 = 4.6 Hz, H-4 );
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁꢁ
2.84 (dd, 1H, J4 ,5 = 6.4 Hz, H-5ꢁ); 2.79 (dd, 1H, J5 ,5 = 12.0 Hz, H-5 );
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁꢁ
ꢁꢁ
ꢁ
2.21 (dd, 1H, J3 ,4 = 4.0 Hz, H-3 ); 1.91 (d, 3H, J = 1.2 Hz, C5-Me);
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
1.72 (ddd, 1H, J3 ,4 = 10.1 Hz, J3 ,3 = 13.5 Hz, H-3 ). Anal. calcd for
C16H17N5O3S(359.4): C, 53.47; H, 4.77; N, 19.49. Found: C, 54.26; H,
4.70; N, 19.29. MS: m/z (FAB) 360 (MH)+.
1-(3-Deoxy-2-S-ethyl-5-S-phenyl-β-D-threopentofuranosyl)thymine
(15). A mixture of 10 (0.30 g, 0.95 mmol), 1 M NaOH (2.4 ml), and 50%
EtOH (20 ml) was stirred at 23◦C for 3 h. The solution was neutralized
with HOAc/EtOH (1:1, v/v) to pH 7.0 and then evaporated to dryness.
The residue was co-evaporated with EtOH (4 × 20 ml) and the residue
was chromatographed on a SiO2 column (10 g) by eluting, in gradient,
with MeOH (0–10%) and CH2Cl2 to give 15 (0.26 g, 83%) as a foam. 1H
NMR (DMSO-d6/D2O): δ 7.58 (s, 1H, H-6); 7.37–7.24 (m, 3H, Ar); 7.01
(m, 2H, Ar); 6.30 (d, 1H, J1 ,2 = 7.3 Hz, H-1ꢁ); 4.71 (m, 1H, H-2ꢁ); 4.46
ꢁ
ꢁ
(m, 1H, H-4ꢁ); 2.81 (dd, 1H, J4 ,5 = 6.3 Hz, H-5ꢁ); 2.70 (dd, 1H, J5 ,5
=
ꢁ
ꢁ
ꢁ
ꢁꢁ
12.1 Hz, H-5ꢁꢁ); 2.20 (m, 1H, H-3ꢁꢁ); 1.91 (s, 3H, C5-Me); 1.75 (m, 1H,
H-3ꢁ). Anal. calcd for C16H18N2O4S (334.4): C, 57.47; H, 5.43; N, 8.38.
Found: C, 57.13; H, 5.32; N, 8.08. MS: m/z (FAB) 357 (MNa)+.
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