Synthesis and synthetic applications of 1-(3-O-tosyl-β-D- glucopyranosyl) thymines: Toward new classes of hexopyranosyl pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2003.12.153

1-(2,4,6-Tri-O-acetyl-3-O-tosyl-β-D-glucopyranosyl) thymine has been synthesized by combining thymine with the appropriate carbohydrate. The availability of this key nucleoside made possible the synthesis of 2,2′-O-anhydro-(4,6-O-phenylmethylene-β-D-altro

Full text of DOI:10.1016/j.tetlet.2003.12.153

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2255–2258
Synthesis and synthetic applications of 1-(3-O-tosyl-b- -
D
glucopyranosyl) thymines: toward new classes of hexopyranosyl
pyrimidines
Sachin G. Deshpandea and Tanmaya Pathakb,*
aOrganic Chemistry Division (Synthesis), National Chemical Laboratory, Pune 411 008, India
bDepartment of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 15 August 2003; revised 9 December 2003; accepted 18 December 2003
Abstract—1-(2,4,6-Tri-O-acetyl-3-O-tosyl-b-
appropriate carbohydrate. The availability of this key nucleoside made possible the synthesis of 2,20-O-anhydro-(4,6-O-phenyl-
methylene-b- -altropyranosyl) thymine and 1-(2,3-O-anhydro-4,6-O-phenylmethylene-b- -mannopyranosyl) thymine. A wide
D-glucopyranosyl) thymine has been synthesized by combining thymine with the
D
D
range of modified hexopyranosyl nucleosides can be easily prepared from these functionalized starting materials.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Although a significant level of interest has been gener-
ated in the synthesis and biological properties of
pentofuranosyl nucleosides over the years,1 the very first
Although the functionalization of hexopyranosyl
nucleosides at the 20, 30, or 40 positions poses major
synthetic challenges, reported methodologies are nar-
rowly focused to prepare only special classes of com-
pounds.2–8 Surprisingly, no serious effort has been made
so far to develop general methodologies for the synthesis
of modified hexopyranosyl nucleosides from common
intermediates as was the case for the pentofuranosyl
nucleosides.1;9 It is, therefore, necessary to develop
general strategies for the synthesis of a wide range of
hexopyranosyl nucleosides.
nucleoside ever synthesized, namely 9-b-
anosyladenine was a hexopyranosyl derivative.2 1-(2-
Deoxy-b- -arabinohexopyranosyl) thymine was recog-
D-glucopyr-
D
nized to be an inhibitor of a pyrimidine nucleoside
phosphorylase.3 Hexopyranosyl nucleosides derived
from allose, altrose, gulose, talose, and mannose have
been synthesized and tested against various micro-
organisms.4 1-(2-Deoxy-6-O-phosphono-b-
D-ribohexo-
pyranosyl)-2,4-pyrimidinedione demonstrated antiviral
and antileukemic activities.5 Synthetic studies on the
pyranosyl nucleoside-based naturally occurring anti-
biotics have also been documented.6 Furthermore, the
synthesis and biological properties of a large number of
pyranosyl azidonucleosides have been reviewed.1 More
recently, the synthesis and biological properties of a new
class of sugar-modified nucleosides derived from 1,5-
anhydrohexitols have been reported.7
The starting materials for the modification of 20- and/or
30-sites of pentofuranosyl pyrimidine nucleosides were
mainly the sulfonylated pyrimidines 1–4, 2,20-O-anhy-
drouridine 5, 2,30-O-anhydrothymidine 6, or the 20,30-O-
anhydronucleosides 7 (Fig. 1).1;9 We envisaged that the
synthesis of selectively tosylated-, epoxy-, or 2,20-O-
anhydronucleosides of the hexopyranosyl type would
pave the way for generating a wide range of unnatural
nucleosides. In the present report, we focus on the
synthesis of three functionalized starting materials,
namely
anosyl) thymine 8, 2,20-O-anhydro-(4,6-O-phenylmeth-
ylene-b- -altropyranosyl) thymine 9, and 1-(2,3-O-
anhydro-4,6-O-phenylmethylene-b- -mannopyranosyl)
thymine 10 (Fig. 2). Intermediates 8, 9, and 10, when
reacted with nonoxygenated nucleophiles, are expected
to generate 30-deoxy-30-modified allo-nucleosides, 20-
1-(2,4,6-tri-O-acetyl-3-O-tosyl-b-
D-glucopyr-
D
Keywords: Hexopyranosyl; Nucleosides; Modified; Allopyranosyl;
Altropyranosyl; Azidonucleosides; Thionucleosides; Aminonucleo-
sides.
D
* Corresponding author. Tel.: +91-3222-283342; fax: +91-3222-2822-
52; e-mail: tpathak@chem.iitkgp.ernet.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.153

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S. G. Deshpande, T. Pathak / Tetrahedron Letters 45 (2004) 2255–2258
O
glucose 13 via 1,2:5,6-di-O-isopropylidene-3-O-p-tolu-
enesulfonyl-a-
-glucofuranose 1413 following a litera-
B
R'O
O
D
N
O
ture procedure used for the synthesis of pentaacetyl
glucose.14 Compound 15 was coupled with bistrimeth-
ylsilylated thymine in the presence of SnCl4 to produce a
single nucleoside 8 in 75% yield (Scheme 1). A large
coupling constant for H10–H20 (J1;2 ¼ 9:3Hz) indicated
the b-configuration of 8.8c Treatment of 8 with isopro-
pylamine in MeOH afforded a clean monoacetyl deriv-
ative 16, which was isolated as the fully protected
benzylidene nucleoside 17. Reaction of 17 with NaOMe/
MeOH produced the highly hygroscopic material 9,
which was identified as its p-nitrobenzoyl derivative 18.
Mesylation of 9 with mesyl chloride in pyridine at 0 ꢁC
afforded 19. The crude mesylated product 19 was con-
verted directly to 20,30-O-anhydro-mannopyranosyl
nucleoside 10 by aq NaOH treatment in 30% overall
yield over the three steps (17 fi 9 fi 19 fi 10; Scheme 2).
O
N
R'O
X
Y
1 B = T; X = OTs/OMs; Y = H
2 B = U; X = OH; Y = OTs
3 B = U; X = OTs; Y = OH
4 B = U; X = Y = OTs/OMs
OR''
O
5
N
O
U/T
N
R'O
R'O
O
O
O
6
7
R',R2'' = protecting groups
Figure 1.
O
O
O
N
HO
O
OTs
O
i)
O
O
HO
O
O
HO
Ph
OH
ii)
AcO
AcO
N
OH
O
O
T
13
TsO
O
OAc
OH
14
9
8
AcO
AcO
TsO
O
R'O
R''O
iii)
OAc
iv)
O
OH
8
T
OAc
HO
O
O
T
Ph
O
15
O
11 R' = R'' = H
12 R', R'' = PhCH
10
Scheme 1. Reagents and conditions: (i) FeCl3, acetone, reflux, 5 h,
70%; (ii) TsCl, py, rt, 2.5 d, 90%; (iii) a. 0.5 N H2SO4, dioxane, reflux,
5 h; b. NaOAc, Ac2O (crude 70%, crystal 40%); (iv) 2,4-di-O-trimethyl-
silylthymine, SnCl4, dichloroethane, 50 ꢁC, 75%.
Figure 2.
deoxy-20-modified allo-nucleosides, and 30-deoxy-30-
modified altro-nucleosides, respectively.
i)
ii)
HO
HO
TsO
O
8
The accessibility to all three compounds 8, 9, and 10 is
crucially dependent on the selective tosylation of the 30-
hydroxyl group of the tetrol 11 or the partially protected
diol 12 had these latter compounds been used as starting
materials.10 Furthermore, for the synthesis of hexopyr-
anosyl thymine, the selection of a glucose derivative was
vital because a ÔdownÕ 2-O-acetyl group would control
the configuration of the glycosidic bond by blocking the
bottom of the pyranosyl ring through neighboring
group participation. However, it was reported that the
T
OAc
16
O
iii)
O
Ph
T
O
TsO
OAc
17
O
N
O
vi)
attempted selective tosylation of methyl b-D-glucopyr-
10
O
O
Ph
anoside derivatives did not produce the required 3-O-
tosylated compounds.11 We expected that the same
trend of tosylation would be followed in the case of
compounds 11 or 12 (Fig. 2). Therefore, in the absence
of any suitable methodology for the selective tosylation
of the 3-hydroxyl group of b-D-glucopyranosides we
decided to incorporate the tosyl group in the sugar
moiety prior to the synthesis of the nucleoside.
N
O
OR
9 R = H
18 R = PNBZ
19 R = Ms
iv)
v)
Scheme 2. Reagents and conditions: (i) isopropylamine, MeOH, rt,
5 h; (ii) PhCH(OCH3)2, TsOH, DMF, 100 ꢁC, 1.5 h, 70% (in two steps);
(iii) NaOMe, MeOH, rt, 30 h; (iv) p-NO2C6H4COCl, py, 0 ꢁC to rt,
overnight, 65%; (v) MsCl, py, +4 ꢁC, overnight; (vi) 2.5 M NaOH,
dioxane, rt, 0.5 h, 30% (in three steps; 17 fi 9 fi 19 fi 10).
For this purpose, 1,2,4,6-tetra-O-acetyl-3-O-tosyl-b-
D-
glucopyranose 1512 was prepared in large scale from

S. G. Deshpande, T. Pathak / Tetrahedron Letters 45 (2004) 2255–2258
2257
In order to establish the usefulness of these new hexo-
OR
O
i)
O
O
pyranosyl nucleosides, 8 was subjected to nucleophilic
displacement. Problems associated with any loss of
acetyl groups were circumvented by reacetylating the
product mixture. Thus, a DMF solution of 8 was treated
with NaOAc at 150 ꢁC for 20 h and the resulting mixture
of products was acetylated. A typical work-up and
Ph
T
10
ii)
N
O
25 R = H
purification yielded 1-(2,3,4,6-tetra-O-acetyl-b-D-allo-
26 R = PNBz
pyranosyl) thymine 20 in 70% yield. Although the syn-
thesis of allopyranosyl thymine had been reported
earlier,8a the present work is the first report on the
conversion of a versatile intermediate such as 8 into an
allopyranosyl nucleoside. Since this route to allopyr-
anosyl thymine derivatives is expected to be general in
nature, treatment of compound 8 with LiN3 in DMF at
120 ꢁC for 20 h followed by reacetylation gave 1-(2,4,6-
Scheme 4. Reagents and conditions: (i) morpholine, DMSO, 90 ꢁC,
25 h, 80%; (ii) p-NO2C6H4COCl, py, rt, 5 h, 80%.
of the mannoepoxide 10 would not have been possible
without the formation of 9. The usefulness of the epoxy
nucleoside 10 has been exemplified by synthesizing a
new deoxyaminonucleoside 25. Moreover, the easy
availability of 24 and 25 would enable us to broaden the
scope of our studies on aminonucleosides1 and vinyl
sulfone-modified nucleosides.15 Research is currently in
progress to study the widest possible application of these
intermediates for the synthesis of an array of new
hexopyranosyl nucleosides.16
tri-O-acetyl-3-azido-3-deoxy-b-
D
-allopyranosyl)
thy-
mine 21 in 61% yield. Compound 21 is the first of its
kind to be reported. Similarly, treatment of 8 with
Na(p)STol in DMF at 90 ꢁC, followed by acetylation
afforded
1-(2,4,6-tri-O-acetyl-3-deoxy-3-S-tolyl-b-D-
allopyranosyl) thymine 22 in 70% yield. In a different set
of experiments the mixture of products obtained from
the reaction of 8 with the sodium salt of p-tolylthiol, was
deacetylated using NaOMe in methanol to give 23. A
DMF solution of 23 was benzylidenated using a stan-
dard procedure to afford 24 in 65% overall yield in three
steps (Scheme 3). The 20,30-O-anhydro hexopyranosyl
thymine 10 was also subjected to nucleophilic ring
opening reactions. Thus, a DMSO solution of 10 was
treated with morpholine at 90 ꢁC for 25 h. A single
compound, the 30-deoxy-30-N-morpholino-altropyrano-
syl nucleoside 25 was obtained in 80% yield, which was
identified as its p-nitrobenzoyl derivative 26 (Scheme 4).
Acknowledgements
T.P. thanks the DST, New Delhi, India for financial
support. S.G.D. thanks CSIR, New Delhi, India for a
fellowship. Both the authors thank Dr. M. S. Shashi-
dhar for his support and interest in this work.
In conclusion, we have devised a methodology for the
synthesis of a strategically tosylated hexopyranosyl
nucleoside 8, which can be easily transformed into sev-
eral allopyranosyl nucleosides. Moreover, 8 can be
transformed into two other extremely important key
synthons 9 and 10. It should be noted that the synthesis
References and notes
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RO
O
i) or, ii) or, iii)
RO
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8
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X
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O
O
O
T
iv)
Ph
OH
STol(p)
24
Scheme 3. Reagents and conditions: (i) a. NaOAc, DMF, 150 ꢁC, 20 h;
b. Ac2O, py, rt, overnight, 70%; (ii) a. LiN3, DMF, 120 ꢁC, 20 h; b.
Ac2O, py, rt, overnight, 61%; (iii) a. p-TolSH, NaOMe, DMF, 90 ꢁC,
10 h; b. Ac2O, py, rt, overnight, 70%; (iv) a. p-TolSH, NaOMe, DMF,
90 ꢁC, 10 h; b. NaOMe, MeOH, rt, 6 h; c. PhCH(OCH3)2, TsOH,
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