Synthesis of 4′-thionucleosides by 1,3-dipolar cycloadditions of the simplest thiocarbonyl ylide with alkenes bearing electron-withdrawing groups

Article abstract of DOI:10.1016/j.tetlet.2007.05.080

Reactions of the simplest thiocarbonyl ylide with a variety of appropriate alkenes bearing electron-withdrawing substituents afforded the corresponding tetrahydrothiophenes, which could be easily elaborated into hydroxy and hydroxymethyl derivatives and t

Full text of DOI:10.1016/j.tetlet.2007.05.080

Tetrahedron Letters 48 (2007) 4915–4918
Synthesis of 40-thionucleosides by 1,3-dipolar cycloadditions
of the simplest thiocarbonyl ylide with alkenes
bearing electron-withdrawing groups
a
a
Antonino Corsaro,a, Venerando Pistara, Maria Assunta Chiacchio,
*
`
Elisa Vittorinoa and Roberto Romeob
a
`
Dipartimento di Scienze Chimiche, Universita di Catania, viale A. Doria 6, Catania 95125, Italy
Dipartimento Farmaco-Chimico, Universita di Messina, via SS. Annunziata, Messina 98168, Italy
b
`
Received 20 February 2007; revised 27 April 2007; accepted 9 May 2007
Available online 18 May 2007
Abstract—Reactions of the simplest thiocarbonyl ylide with a variety of appropriate alkenes bearing electron-withdrawing substit-
uents afforded the corresponding tetrahydrothiophenes, which could be easily elaborated into hydroxy and hydroxymethyl deriva-
tives and then coupled with nucleobases to produce different 40-thionucleosides. Particularly, a- and b-anomers of 1-[3,4-
bis(hydroxymethyl)tetrahydro-2-thienyl]-thymine, -cytosine, -uracil and -fluorouracil were prepared with dimethyl fumarate and
maleate, while 1-[4-(hydroxymethyl)tetrahydro-2-thienyl]- and 1-[4-(hydroxymethyl)tetrahydro-3-thienyl]-thymine, -cytosine, -uracil
and -fluorouracil were prepared with a chiral a,b-unsaturated amide. These processes, simple in the experimental conditions and
large availability of the starting materials, affording moderate to good yields of 40-thionucleosides, represent an optimum alternative
to those, already known, based on sugars, which often have the drawbacks of a higher number of steps and lower yields.
Ó 2007 Elsevier Ltd. All rights reserved.
In the past 15 years, a wide variety of nucleoside ana-
logues, modified in the carbohydrate moiety and/or in
the nucleobase, have been prepared and tested for anti-
viral and antitumoural activities.1 One of the first mod-
ifications was the isosteric substitution of the oxygen
atom with a sulfur atom in furanonucleosides of adenine
affording the corresponding 40-thio-derivatives.2 These
40-thionucleosides showed potent anti-herpes activities,
and several other analogues, such as 40-thiothymidine
and 20-deoxy-40-thiocytidine, exhibited potent cytotoxic-
ity. On a chemical level, it was envisaged that this mod-
ification would modulate stereoelectronic and steric
effects in the tetrahydrothiophene moiety. Evidences
were accumulating that the presence of a sulfur atom
in the sugar ring stabilized the N-glycosidic bond with
respect to phosphorolysis.3 Thus 40-thioinosine was
known to be resistant to phospholytic cleavage, which
is a normal pathway in nucleoside catabolism. This is
a major advantage of 40-thionucleosides, since several
‘40-oxy’ antivirals have a drawback with regard to their
metabolic stability caused by nucleoside phosphoryl-
ases. In addition, the potent antiviral activity and cyto-
toxicity of 40-thionucleosides suggest that they are well
recognized as substrates by both viral and host cell
kinases.
Frequently, synthetic approaches to 40-thionucleosides
have made use of displacement reactions of a sugar leav-
ing group with a sulfur-containing nucleophile, followed
by ring closure or ring contraction,4 acetolysis of a sugar
c,c-diethoxy episulfide, or ring closure of sugar dialkyl
dithioacetal,5 since the initial stereochemistry of sugars
directly controls that one of the final products through
stereo-specific or -selective steps.
In addition to sugars or their derivatives, only a few
non-sugar starting materials, such as protected thio-
phenes,6 L-glyceraldehyde,7 chiral thiolactones,8 or (S)-
(ꢀ)-glycitol,9 have been used.
Keywords: Thionucleosides; 1,3-Dipolar cycloaddition; Thiocarbonyl
ylide; Antiviral.
*
However, since tetrahydrothiophene syntheses starting
from sugars have often met various difficulties, among
Corresponding author. Tel.: +39 095 7385017; fax: +39 095
580138; e-mail: acorsaro@unict.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.080

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A. Corsaro et al. / Tetrahedron Letters 48 (2007) 4915–4918
Table 1. Yieldsa (%) and anomeric ratiosb of 8, 9a–d and 10, 11a–d
which, for example, the frequent involvement of many
steps, and on the basis of our experiences on the nitrile
oxide and nitrone chemistry in the construction of N,O-
nucleosides,10 we planned to synthesize the tetrahydro-
thiophene moiety via a practical method involving the
1,3-dipolar cycloaddition of the simplest thiocarbonyl
ylide 1,11 to a variety of appropriate alkenes bearing
electron-withdrawing substituents such as commercially
available methyl fumarate 2 and maleate 12. From their
tetrahydrothiophene adducts 3 and 13,12 40-thionucleo-
sides were then constructed by conventional synthetic
methods, among which the coupling reaction of the cor-
responding sulfoxides with a persilylated nucleobase is
largely applied in most approaches.13 This thiogly-
cosylation reaction is based on the sila-Pummerer-type
reaction,14 even if it presents the drawback of the poor
b-selectivity. The undesired a-isomer is, almost always,
the main product, while the b-anomer is formed in ex-
cess only in the presence of a neighbouring group of
an adjacent acyloxy or benzyloxy group.15 In addition,
by using (E)-3-benzoyloxypropenoyl-(1S)-camphorsul-
tam 19 with 1, tetrahydrothiophene rings 20 and 2116
were obtained, from which the construction of the de-
sired 40-thionucleosides bearing the nucleobase and the
hydroxymethyl group in positions 3 and 4 or 2 and 4,
respectively, was achieved. As first noted, besides thy-
mine and cytosine, uracil and its 5-fluoro derivative were
also used as nucleobases.
Nucleobase
8+9
8:9
10
11
Thymine 7a
Cytosine 7bc
Uracil 7c
5-F-Uracil 7d
Adenine 7ed
78.0
72.0
80.0
79.0
68.0
1:18
1:15
1:20
1:18
1:12
4.0
4.0
3.0
4.0
5.0
73.5
67.5
76.0
74.0
62.5
a Isolated yields based on 6.
b Determined by 1H NMR spectroscopy.
c Cytosine was used as N-benzoyl derivative until the last step.
d Adenine was used as 6-chloro derivative, which was aminated in the
last step.
After the oxidation of 3,4-dibenzoyltetrahydrothio-
phene derivative 5 with m-CPBA into sulfoxide 6, the
subsequent Pummerer-type reaction performed in the
presence of nucleobases 7a–d, as silylated derivatives,
trimethylsilyl triflate and triethylamine, provided a mix-
ture of corresponding 40-thionucleosides 8a–d and 9a–d
with the prevalence of b-anomers9 9a–d for which a con-
trol attributable to the participation of the neighbouring
benzoyloxy group can be invoked, while a-anomers9
8a–d were obtained in very low yields (Table 1). The puri-
fication of anomeric mixture by means of preparative
HPLC and subsequent deprotection of hydroxyl groups
with methanolic ammonia gave b-anomers 11a–d in
moderate to good yields (Table 1). The structures and
stereochemistry of 10a–d and 11a–d were assigned on
the basis of their analytical data and 1H and 13C
NMR spectra. Particularly, NOE experiments easily
allowed the assignation of their anomeric configurations.
Irradiation of 2-H proton in b-anomers 11a–d gave a
NOE enhancements (1.3–1.6%) on methylene protons
of C4-hydroxymethyl groups, while no NOE effect was
observed on the same experiments about a-anomers
10a–d.
The reaction of 1, generated by CsF decomposition17 of
the very easy to synthesize chloromethyltrimethylsilyl-
methyl sulfide,18 with methyl fumarate (2) afforded
trans-dimethyl tetrahydrothiophene-3,4-dicarboxylate
(3),8 which was reduced to diol 4 by LiAlH4, and then
converted into 5 by protection with benzoyl chloride
(Scheme 1).
40-Thioadenosine b-11e was also synthesized (Scheme 1)
in order to compare the results of our method with that
one of Kato and co-workers,19 who, starting from (+)-
diethyl L-tartrate, synthesized (S,S)-1,4-bis(benzoyl-
oxy)-2,3-epoxy-butane according to the protocol of
Nicolaou et al.20 and from this latter, b-11e, but through
13 steps and in a low yield (38%).
By following the same sequence of reactions, but with
methyl maleate 1221 instead of fumarate 2 (Scheme 2),
mixtures of isomers 15a–d and 16a–d were obtained in
a good yield (Table 2). Their separation by means of
HPLC and finally their hydrolysis with methanolic
ammonia gave 17a–d and 18a–d in the yields reported
in Table 2.
NOE experiments allowed to achieve, also in this case,
the stereochemistry of isolated nucleosides 17a–d and
18a–d: the irradiation of H-3 protons caused the
enhancement of H-2 and H-1 protons in 17a–d,
and the enhancement of only H-2 proton in 18a–d.
The a-anomers9 18a–d were isolated as prevalent ano-
mers because of the participation of the neighbouring
benzoyloxy group, which directs the attack to their
opposite ring face.
Scheme 1. Reagents and conditions: (i) Me3SiCH2SCH2Cl, CsF,
CH3CN, 0 °C, overnight; (ii) LiAlH4, THF, 0 °C, 1 h; (iii) BzCl, Py,
rt, 2 h; (iv) m-CPBA, CH2Cl2, ꢀ40 °C; (v) silylated nucleobase (7a–e),
TMSOTf, Et3N, CH2Cl2, PhMe, rt, overnight; (vi) NH3 concd,
MeOH, rt, 12 h.

A. Corsaro et al. / Tetrahedron Letters 48 (2007) 4915–4918
4917
Scheme 2. Reagents and conditions: (i) Me3SiCH2SCH2Cl, CsF,
CH3CN, 0 °C, overnight; (ii) LiAlH4, THF, 0 °C, 1 h; (iii) BzCl, Py,
rt, 2 h; (iv) m-CPBA, CH2Cl2, ꢀ40 °C; (v) silylated nucleobase (7a–d),
TMSOTf, Et3N, CH2Cl2, PhMe, rt, overnight; (vi) NH3 concd,
MeOH, rt, 12 h.
Scheme 3. Reagents and conditions: (i) Me3SiCH2SCH2Cl, CsF,
CH3CN, 0 °C, overnight; (ii) LiAlH4, THF, 0 °C, 1 h; (iii) TBDPSCl,
DMAP, Et3N, rt, 12 h; (iv) H2, Pd/C, AcOEt, rt, 4 h; (v) TsCl, Py, rt,
24 h; (vi) silylated nucleobase (7a–d), 18-Crown-6, K2CO3, DMF,
100 °C, 18 h; (vii) TBAF, THF, rt, 1 h.
Table 2. Yieldsa (%) and anomeric ratiosb of 15, 16a–d and 17, 18a–d
Base
15+16
15:16
17
18
Table 3. Yieldsa (%) of enantiomerically pure protected nucleosides
26a–d
Thymine 7a
Cytosine 7bc
Uracil 7c
80.0
74.0
83.0
81.0
1:18
1:16
1:20
1:18
75.0
69.0
79.0
76.0
4.0
4.0
3.0
4.0
Base
26
Thymine 7a
Cytosine 7bb
Uracil 7c
46.0
45.0
38.0
40.0
5-F-Uracil 7d
a Isolated yields based on 14.
b Determined by 1H NMR spectroscopy.
c Cytosine was used as N-benzoyl derivative until the last step.
5-F-Uracil 7d
a Isolated yields based on 25.
b Cytosine was used as N-benzoyl derivative until the last step.
The generation of thiocarbonyl ylide 1 in the presence of
the enantiopure (E)-3-benzoyloxypropenoyl-(1S)-cam-
phorsultam 19 afforded the two diastereomeric adducts
20 and 21 in excellent yield (92%) and high diastereose-
lectivity (20:21 = 1:9).12 The two adducts were separated
by silica gel column chromatography, and then the
chiral camphorsultam inductor was removed from 21
by reduction with LiAlH4 at 0 °C to give 22, which
was protected with tert-butyldiphenylsilyl chloride
(TBDPSCl) affording 23. The debenzylation of 23 into
24 and subsequent activation of the hydroxy group for
SN2 displacement gave tosylate 25. Reactions of 25 with
anions22 of nucleobases 7a–d afforded protected nucleo-
sides 26a–d which, finally, were desilylated with TBAF/
THF to give enantiopure thionucleosides 27a–d (Scheme
3, Table 3). The structure of 27a–d was confirmed from
analytical and spectroscopic data and stereochemistry
was assigned with the aid of NOE experiments, which
indicated an enhancement of 14.5% between H-3 and
H-4 protons.
In addition, the tosyl derivative 25 was subjected to an
other process including the elimination of the tosylate
group with NaH in DMF to produce the protected
4-hydroxymethyl thioglycal 28. The addition of phenyl-
selenyl chloride and nucleobases 7a–d, as silylated
derivatives, to 28 provided adducts 29 and 30 as ano-
meric mixtures in satisfying yield from which subse-
quently the phenylselenyl substituent was eliminated to
give 31 and 32 by radical reduction with tributyltin
Scheme 4. Reagents and conditions: (i) NaH, DMF, 0 °C–rt, 3 h; (ii)
PhSeCl, silylated nucleobase (7a–d), CH3CN, 0 °C, 3 h; (iii) TBAF,
THF, rt, 30 min; (iv) Bu3SnH, Et3B, O2, PhMe, rt, 12 h.
hydride and triethyl borane at ꢀ78 °C in the presence of
a continuous flow of oxygen (Scheme 4). In this way,
desired a- and b-thioapionucleosides 33 and 3423 (Table
4) were obtained with good diastereoselectivity accord-

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A. Corsaro et al. / Tetrahedron Letters 48 (2007) 4915–4918
Table 4. Yieldsa (%) and anomeric ratiosb of 29, 30a–d, 31, 32a–d and
33, 34a–d
T., Bertino, J., Eds.; Academic Press: New York, 1981; p
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Nucleobase
29+30 29:30 31+32 31:32 33 34
Thymine 7a
Cytosine 7bc
Uracil 7c
82.0
74.0
84.0
1:10
1:6
1:12
1:8
64.0
61.0
69.0
66.0
1:9
1:6
1:10
1:8
4.0 47.0
5.0 36.0
5.0 52.0
4.0 45.0
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5-F-Uracil 7d 80.0
a Isolated yields based on 28.
b Determined by 1H NMR spectroscopy.
c Cytosine was used as N-benzoyl derivative until the last step.
6. Rassu, G.; Spanu, P.; Pinna, L.; Zanardi, F.; Casiraghi, G.
Tetrahedron Lett. 1995, 36, 1941–1944.
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ing to Haraguchi et al.24 and then with a process that
registers a minor number of simpler steps with respect
to that one of Jeong and co-workers.25
In conclusion, this strategy of thiocarbonyl ylide cyc-
loadditions leading to suitable tetrahydrothiophene
rings, which are coupled with a nucleobase, provides
an unprecedented and convenient route to different 40-
thionucleosides. It is based on the ready accessibility
of the starting materials for the thiocarbonyl ylide prep-
aration, and, above all, for the simplicity of the moder-
ate to good conversion of [3+2] cycloadditions.
Investigations on the antiviral and antitumoural activi-
ties of these and several other nucleosides will be the ob-
ject of a next work. Particularly, in addition to reactions
with alkenes bearing other different electron-withdraw-
ing groups, reactions of the a-hydroxymethyl substi-
tuted thiocarbonyl ylide will be investigated in order
to examine the stereochemical outcome due to a chiral
1,3-dipole, if necessary in the presence of chiral auxilia-
ries, by which the control of the stereochemistry can be
effected.
11. For a review, see: Kellog, R. M. Tetrahedron 1976, 32,
2165.
12. Hosomi, A.; Matsuyama, Y.; Sakurai, H. J. Chem. Soc.,
Chem. Commun. 1986, 1073.
13. These thionucleosides were distinguished in a- (trans) and
b-anomers (cis) in relation to the reciprocal position of the
C2-nucleobase and C4-hydroxymethyl group.
14. (a) Kita, Y.; Yasuda, H.; Tamura, O.; Itoh, F.; Tamura,
Y. Tetrahedron Lett. 1984, 25, 4681–4682; (b) Kita, Y.;
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cited therein; (b) Naka, T.; Nishizono, N.; Minakawa, N.;
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references cited therein.
16. Karlson, S.; Ho¨gberg, H.-E. Org. Lett. 1999, 1, 1667–
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Financial supports from the University of Catania and
Messina, and from MIUR (Rome), in the framework
of COFIN 2006 program are gratefully acknowledged.
19. Kikuchi, Y.; Kurata, H.; Nishiyama, S.; Yamamura, S.;
Kato, K. Tetrahedron Lett. 1997, 38, 4795–4798.
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23. In addition to analytical and spectroscopic data, their
configurations were achieved by comparison with results
of 1H NOE experiments on the same compounds, with the
exception of 5-F-uracil, reported by Jeong and co-workers
(see Ref. 25).
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