Simple entry into isonucleosides: Synthesis of 6-amino-9-[(3S,4S,5R)-4- hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl]purine

Article abstract of DOI:10.1016/j.tetlet.2004.02.021

A simple and efficient method for the preparation of isonucleoside 7 is described. The preparation of 1,4-anhydroxylitol 4, a key intermediate, is described by intramolecular cyclization of (2S,3R,4R)-3,5-dibenzyloxypentan-1,2, 4-triol 3 using diethyl car

Full text of DOI:10.1016/j.tetlet.2004.02.021

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2965–2966
Simple entry into isonucleosides: synthesis of 6-amino-9-
[(3S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-
furan-3-yl]purine
Hari Babu Mereyala* and Sreeman Kumar Mamidyala
Speciality, Gas Based Chemicals and Processes Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
Received 16 November 2003; revised 30 January 2004; accepted 5 February 2004
Abstract—A simple and efficient method for the preparation of isonucleoside 7 is described. The preparation of 1,4-anhydroxylitol
4, a key intermediate, is described by intramolecular cyclization of (2S,3R,4R)-3,5-dibenzyloxypentan-1,2,4-triol 3 using diethyl
carbonate and NaH.
Ó 2004 Published by Elsevier Ltd.
NH2
N
A number of nucleoside analogues have been found to
possess antiviral and anticancer activities.1 Modification
of the sugar part of nucleosides has led to the develop-
ment of several nucleoside analogues including dide-
NH2
N
N
N
N
N
N
HO
N
OH
oxynucleosides2
[AZT
(3-azidothymidine),
ddC
O
O
(dideoxycytidine), ddI (dideoxyinosine), carbocyclic
nucleosides3 (Carbovir), acyclic nucleosides4 (Acyclovir
and Ganciclovir). The natural nucleosides and nucleo-
tides as well as many synthetic nucleosides, which are of
therapeutic use are quite susceptible to both hydrolytic
and enzymatic cleavage where nucleobases are attached
to C-1 of the sugar moiety. In the search for modified
nucleosides, which can resist hydrolysis and enzymatic
degradation, there is considerable interest in the inves-
tigation of isonucleosides in which the nucleobase is
linked to a position on the sugar moiety other than C-1.5
Isonucleosides, which have proved to have therapeutic
value against a broad spectrum of viruses and some
tumor cell lines include both stereomers of, for example,
(S,S)-iso-ddA6 and its enantiomer (R,R)-iso-ddA7 (Fig.
1).
(S,S)-iso-ddA
(R,R)-iso-ddA
Figure 1.
acid8 to obtain the anhydro derivatives.9 The tetra-
hydrofurans have also been synthesized through proto-
cols involving ring opening–ring closing of sugar
precursors or through asymmetric synthesis from pro-
chiral starting materials.10 Bis-epoxides11 and glycidol,12
obtained by asymmetric synthesis, have been used for
the synthesis of isonucleosides using iodo etherification
as a key step. Butane-1,2,4-triol was used to synthesize
1,4-anhydroalditol stereoselectively using desilylation
with NH4F and concomitant cyclization.13 The nucleo-
base can also be directly introduced by nucleophilic
substitution of a sulfonate with nucleobase salts.14 1,4-
The 1,4-anhydroalditol moieties in isonucleosides are
usually prepared from carbohydrates through multi-step
reactions. The most common strategy has been reduc-
tion of methyl glycofuranosides or 1,2-O-isopropylidene
glycofuranoses by reaction with triethylsilane/Lewis
Anhydro-3,5-di-O-benzyl-D-ribitol was prepared by
cyclization of (2S,3S,4R)-3,5-dibenzyloxypentan-1,2,4-
triol by a Mitsunobu reaction (DEAD/TPP) in THF.9
In continuation of our investigations toward the syn-
thesis of modified nucleosides,15 we report here a simple
and efficient method for the synthesis of 6-amino-9-
[(3S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofu-
ran-3-yl]purine 7 (Scheme 1). The key intermediate,
Keywords: Isonucleosides; Alditol; Nucleobase.
* Corresponding author. Tel.: +91-40-27193137; fax: +91-40-271609-
21; e-mail: mereyalahb@rediffmail.com
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.02.021

2966
H. B. Mereyala, S. K. Mamidyala / Tetrahedron Letters 45 (2004) 2965–2966
by intramolecular cyclization using diethyl carbonate/
NaH/THF is described.
BnO
ref.16
BnO
i
OBn
OBn
O
O
ii
OH
D-xylose
O
O
OH
1
2
NH2
N
Acknowledgements
N
S.K.M. is thankful to the Council of Scientific and
Industrial Research (CSIR, New Delhi) for financial
support in the form of a senior research fellowship.
BnO
iii
OR
O
N
OBn
RO
v
N
OBn
O
BnO
OH
OH OH
OR
6 R=Bn
7 R=H
4 R=H
5 R=tosyl
3
iv
vi
References and notes
Scheme 1. Reagents and conditions: (i) IR-120 (Hþ) resin, H2O, 90 °C,
5 h, 95%; (ii) NaBH4, MeOH, rt, 4 h, 88%; (iii) EtOCO2Et
(2 mol equiv), THF, NaH, reflux, 3 h, 83%; (iv) tosyl chloride, pyridine,
CH2Cl2, rt, 4 h, 98%; (v) adenine (2 mol equiv), 18-crown-6
(1.2 mol equiv), DMF, 100 °C, 16 h, 58%; (vi) 10% Pd/C, H2, rt, 12 h,
MeOH, 93%.
1. (a) De Clercq, E. In Approaches to Antiviral Agents;
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Rep. Med. Chem. 1989, 24, 129–137.
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D. W.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1985, 82,
7096–7100; (b) Mitsuya, H.; Broder, S. Proc. Natl. Acad.
Sci. U.S.A. 1986, 83, 1911–1915.
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Trans. 1 1992, 1427–1439; (b) Soike, K. F.; Whiterock, V.
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S. Antimicrob. Agents Chemother. 1995, 39, 1017–1029.
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Nucleotides 1994, 13, 109–126; (b) Zhang, J.; Nair, V.
Nucleosides, Nucleotides 1997, 16, 1091–1094; (c) Talekar,
R. R.; Wightman, R. H. Nucleosides, Nucleotides 1997, 16,
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T.; Matsuda, A. Tetrahedron 1994, 34, 10167–10182.
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L.-H. Tetrahedron: Asymmetry 1997, 8, 2739–2747; (b)
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2981.
1,4-anhydro-3,5-di-O-benzyl-
prepared from 3,5-di-O-benzyl-1,2-O-isopropylidene-a-
-xylofuranose 1.16 Compound 1, on reaction with IR-
120 (Hþ) resin in water at 90 °C for 5 h resulted in the
formation of 3,5-di-O-benzyl- -xylofuranose 2. Reduc-
D-xylitol was elegantly
D
D
tion of 2 with NaBH4/MeOH gave (2S,3R,4R)-3,5-di-O-
benzyloxypentan-1,2,4,-triol 3. Stereoselective cyclization
of triol 3 using diethyl carbonate and NaH in THF
at reflux for 3 h resulted in the formation of 1,4-anhy-
dro-3,5-di-O-benzyl-D-xylitol 4 as a syrup in 83%
1
yield.17 Compound 4 was characterized by its H NMR
spectrum from the appearance of H-2 at d 3.80 (dd,
J ¼ 11:0, 3.7 Hz), H-20 at d 4.08 (dd, J ¼ 11:0, 3.1 Hz),
and H-3 at d 4.12 as a multiplet.
Compound 4 on tosylation gave the corresponding
derivative 5 in quantitative yield, which was character-
1
ized by H NMR analysis from the appearance of H-2
and H-20 at d 3.80 and d 4.14, respectively, as multiplets
and H-3 at d 5.00 as a multiplet shifted downfield.
Reaction of derivative 5 with adenine in the presence of
K2CO3/18-crown-6 in DMF at 100 °C for 16 h resulted
in the formation of 6-amino-9-[(3S,4S,5R)-4-benzyloxy-
5-(benzyloxymethyl)tetrahydrofuran-3-yl]purine
6
in
58% yield as a solid, mp 162–164 °C. Compound 6 was
characterized by 1H NMR analysis from the appearance
of H-20 at d 4.20 (dd, J ¼ 11:4, 3.5 Hz), H-200 at d 4.45
(dd, J ¼ 11:4, 3.2 Hz), and H-30 at d 5.25 as a multiplet
and by its 13C NMR spectrum from the appearance of
C-20 at d 68.4 and C-30 at d 82.4. Reductive debenzyl-
ation (10% Pd/C/H2/MeOH/rt) of 6 for 12 h resulted in
the formation of 6-amino-9-[(3S,4S,5R)-4-hydroxy-5-
12. Diaz, Y.; Bravo, F.; Castillon, S. J. Org. Chem. 1999, 64,
6508–6511.
13. Zheng, X.; Nair, V. Tetrahedron 1999, 55, 11803–11818.
14. Bera, S.; Nair, V. Tetrahedron Lett. 2001, 42, 5813–5815.
15. Mereyala, H. B.; Mamidyala, S. K. Nucleosides, Nu-
cleotides (2004, in press).
16. (a) Levene, P. A.; Raymond, A. L. J. Biol. Chem. 1933,
102, 317–330; (b) De Belder, A. N. Adv. Carbohydr. Chem.
Bio. Chem. 1977, 34, 179–241.
17. Montgomery, J. A.; Thomas, H. J. J. Org. Chem. 1978, 43,
541–544.
(hydroxymethyl)tetrahydrofuran-3-yl]purine
solid, mp 260 °C (dec).
7
as
a
In summary, a simple method for obtaining 1,4-anhy-
droxylitol 4, a key intermediate required for the syn-
thesis of isonucleoside 7 from the corresponding triol 3