Stereoselective synthesis of L-isonucleosides

Article abstract of DOI:10.1016/S0040-4039(03)00743-3

L-Isonucleosides 17 and 19 were stereoselectively synthesised from (S)-glycidol by two different procedures. The key step was the synthesis of a chiral dihydrofuran which was carried out by oxidation/elimination of 8 and by ring-closing metathesis of dien

Full text of DOI:10.1016/S0040-4039(03)00743-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3771–3773
Stereoselective synthesis of -isonucleosides
L
S´ılvia Aragone`s, Fernando Bravo,* Yolanda D´ıaz, Ma6 Isabel Matheu and Sergio Castillo´n*
Departament de Qu´ımica Anal´ıtica i Qu´ımica Orga`nica, Universitat Rovira i Vigili, Pl. Imperial Tarraco 1, 43005 Tarragona,
Spain
Received 21 February 2003; revised 19 March 2003; accepted 20 March 2003
Abstract—L-Isonucleosides 17 and 19 were stereoselectively synthesised from (S)-glycidol by two different procedures. The key
step was the synthesis of a chiral dihydrofuran which was carried out by oxidation/elimination of 8 and by ring-closing metathesis
of diene 10. The procedure can be applied to the synthesis of both enantiomers. © 2003 Elsevier Science Ltd. All rights reserved.
Although most new nucleoside analogues reported are
-nucleosides, during the last decade -nucleosides
sive study of these isonucleosides, including the syn-
thesis of oligonucleotides.7 However, there are few
D
L
have emerged as a new class of biologically active
compounds.1 Isonucleosides2 are also promising thera-
peutic agents, since some of them combine strong and
selective anti-HIV and anti-HSV activity with higher
stability towards acid and enzymatic degradation. For
example, the (S,S)-isomer of the deoxy-isonucleoside
iso-ddA3 (Fig. 1) has an anti-HIV activity similar to
that of ddA, and no apparent toxicity. Interestingly,
its enantiomer [(R,R)-isomer] has a similar range of
activity. We have recently published a synthesis of
(S,S)-iso-ddA from glycidol which allows both enan-
tiomers to be prepared by choosing the configuration
of the starting material.4
reports describing the synthesis of L-isonucleosides
(2).8
Isonucleosides are synthesised by reacting an activated
1,4-anhydroalditol derivative with the purinic or
pyrimidinic base. The 1,4-anhydroalditol moieties are
usually prepared from carbohydrates (Scheme 1).5–9
D
-Ribose is the starting material for synthesising
-hydroxyderivatives such as 1, through deoxygena-
D
tion of the anomeric position to give derivative 3.
L
-Isonucleosides are prepared from 3,5-di-O-mesyl-
D
-xylose, via a rearrangement to give
L
-sugar 4.8
This is followed by formation of the epoxide 5, which
is opened by a nucleic base. Only a few reports
describe the asymmetric synthesis of 1,4-anhydroaldi-
tol units.10
D
-Isonucleosides (1, Fig. 1) were first prepared by
Montgomery,5 and later Nair6 carried out an inten-
Figure 1.
* Corresponding authors. Tel.: +34-977-559556; fax: +34-977-559563; e-mail: bravo@correu.urv.es; castillon@correu.urv.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00743-3

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S. Aragone`s et al. / Tetrahedron Letters 44 (2003) 3771–3773
Scheme 1.
Continuing with our interest in developing procedures
for the synthesis of both - and -isonucleosides, we
report in this paper the stereoselective synthesis of
-isonucleosides (2) from (S)-glycidol.
D
L
L
Recently, Nair reported an efficient procedure for
introducing nucleic bases by opening a cyclic sul-
fate.11 Bearing this in mind, we decided to obtain the
Scheme 2.
Scheme 3. Reagents and conditions: (a) (CH3)3SI, BuLi, THF, 0°C, 2 h, 69%. (b) 1. NaH, THF, from −18°C to reflux, 2 h, 2.
t
BrCH2CHꢀCH2, rt, 2 h, 92%. (c) Grubbs catalyst, CH2Cl2, rt, 4 h, 78%. (d) K2OsO4·2H2O, NMO, BuOH/DMF, rt: 13, 36 h,
91%, cis:trans=1:9; 14, 3.5 h, 78%, cis:trans=1:4. (e) RuCl3, NaIO4, CH3CN/AcOEt/H2O, −20°C: 13, 3 h, 35%, only trans; 14,
2 h, 70%, cis:trans=1:10. (f) 1. Cl2SO, py, rt, 12 h, 90%, 2. RuCl3, NaIO4, CCl4/CH3CN/H2O, 0°C, 2 h, 88%. (g) Adenine or
thymine, DBU, CH3CN, reflux, 2.5 h, then 15, 2.5 h. (h) 3% HCl in MeOH, reflux, 24 h: 17, 67% (two steps); 19, 62% (two steps).

S. Aragone`s et al. / Tetrahedron Letters 44 (2003) 3771–3773
3773
precursor diol by dihydroxylation of the corresponding
dihydrofuran (Scheme 2).
G.; Placidi, L.; Faraj, A.; Loi, A. G.; Pierra, G.; Dukhan,
D.; Gosselin, G.; Imbach, J. L.; Herna´ndez, B.; Juo-
dawlkis, A.; Tennant, B.; Korba, B.; Cote, P.; Cretton-
Scott, E.; Schinazi, R. F.; Sommadossi, J. P. Nucleosides
Nucleotides 2001, 20, 597–607; (c) Lee, K.; Choi, Y.;
Hong, J. H.; Schinazi, R. F.; Chu, C. K. Nucleosides
Nucleotides 1999, 18, 537–540.
We recently described the synthesis of the enantiopure
dihydrofuran 11 by regioselective elimination of the
selenoxide derived from 8, which in turn had been
obtained in a straightforward manner from glycidol 6
(Scheme 3).12 Some reports describe that stereoselectiv-
ity in the hydroxylation of related compounds depends
on the solvent13 and the substituents in the substrate.14
We explored different reaction conditions for the
hydroxylation of dihydrofuran 11. Treatment with
2. (a) Nair, V.; Jahnke, T. S. Antimicrob. Agents Chemother.
1995, 39, 1017–1029; (b) Nair, V. In Nucleosides and
Nucleotides as Antitumor and Antiviral Agents; Chu, C.
K.; Baker, D. C., Eds.; Plenum Press: New York, 1993;
pp. 127–140.
3. (a) Nair, V.; Nuesca, Z. M. J. Am. Chem. Soc. 1992, 114,
7951–7953; (b) Bolon, P. J.; Sells, T. B.; Nuesca, Z. M.;
Purdy, D. F.; Nair, V. Tetrahedron 1994, 50, 7747–7764.
4. D´ıaz, Y.; Bravo, F.; Castillo´n, S. J. Org. Chem. 1999, 64,
6508–6511.
t
K2OsO4/MNO in BuOH–DMF gave 1,4-anhydroaldi-
tol 13 in 91% yield (cis:trans=1:9). Dihydroxylation
with RuCl3/NaIO4, albeit much faster and selective
(only the trans isomer was isolated) gave a smaller yield
of 13 (35%). This compound is the enantiomer of the
intermediate prepared by Nair in the reported synthesis
of isonucleoside 1.11
5. Montgomery, J. A.; Thomas, H. J. J. Org. Chem. 1978,
43, 541–544.
6. (a) Nair, V.; Buenger, G. S. J. Am. Chem. Soc. 1989, 111,
8502–8504; (b) Purdy, D. F.; Zintek, L. B.; Nair, V.
Nucleosides Nucleotides 1994, 13, 109–126.
7. (a) Wenzel, T.; Nair, V. Bioorg. Med. Chem Lett. 1997, 7,
3195–3198; (b) Wenzel, T.; Nair, V. Bioconjugate J. 1998,
9, 683–690.
On the other hand, in recent years the metathesis
reaction15 has emerged as an efficient synthetic method-
ology for preparing unsaturated cycles of medium and
large size, and we decided to use it to prepare the
dihydrofuran intermediate.
8. (a) Yu, H. W.; Zhang, L. R.; Zou, J. C.; Ma, L. T.;
Zhang, L. H. Bioorg. Med. Chem. 1996, 4, 609–614; (b)
Talekar, R. R.; Wightman, R. H. Tetrahedron 1997, 53,
3831–3842.
9. (a) Jones, M. F.; Noble, S. A.; Robertson, C. A.; Storer,
R.; Highcok, R. M.; Lamont, R. B. J. Chem. Soc., Perkin
Trans. 1 1992, 1427–1436; (b) Nuesca, Z. M.; Nair, V.
Tetrahedron Lett. 1994, 35, 2485–2488; (c) Zhang, J.;
Nair, V. Nucleosides Nucleotides 1997, 16, 1091–1094; (d)
Talekar, R. R.; Wightman, R. H. Nucleosides Nucleotides
1997, 16, 495–505.
Thus, we started from glycidol 7 and chose the trityl
protecting group in order to deprotect it during the acid
treatment subsequent to the sulfate opening. Treatment
of 7 with the sulfur ylide CH2ꢀSMe2 gave the butene-
diol 9 in 69% yield.16 Subsequent allylation of 9 with
allyl bromide in basic medium afforded the diene 10 in
excellent yield. The diene 10 was then submitted to a
RCM process by reaction with RuCl2(CHC6H5)-
[P(C6H11)3]2 to give dihydrofuran 12 in 78% yield.17,18
Then we treated 12 with K2OsO4·2H2O/NMO to obtain
the 1,4-anhydroalditol 14 in 78% yield in a cis:trans
ratio of 1:4. In this case, the dihydroxylation with the
RuCl3/NaIO4 system furnished 14 in 70% yield
(cis:trans=1:10).
10. (a) Zheng, X.; Nair, V. Tetrahedron 1999, 55, 11803–
11818; (b) Jung, M. E.; Nichols, C. J. J. Org. Chem. 1998,
63, 347–355; (c) Bravo, F.; D´ıaz, Y.; Castillo´n, S. Tetra-
hedron: Asymmetry 2001, 12, 1635–1643.
Sulfate 15 was obtained by treating 14 with thionyl
chloride and further oxidation with RuCl3–NaIO4.11
The bases were introduced following the procedure
described by Nair to give the compounds 16 and 18,
which were directly submitted to acid treatment to
provide the isonucleosides 17 and 19 in 67 and 62%
yield, respectively.
11. Bera, S.; Nair, V. Tetrahedron Lett. 2001, 42, 5813–
5815.
12. Bravo, F.; Viso, A.; Castillo´n, S. J. Org. Chem. 2003, 68,
1172–1175.
13. (a) Trost, B. M.; Kallander, L. S. J. Org. Chem. 1999, 64,
5427–5435; (b) Gudmundsson, K. S.; Drach, J. C.;
Townsend, L. B. J. Org. Chem. 1998, 63, 984–989.
14. Donohoe, T. J.; Mitchell, L.; Waring, M. J.; Helliwell,
M.; Bell, A.; Newcombe, N. J. Tetrahedron Lett. 2001,
42, 8951–8954.
Acknowledgements
15. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29.
16. Baylon, C.; Heck, M. P.; Mioskowski, C. J. Org. Chem.
1999, 64, 3354–3360.
17. (a) Davoille, R. J.; Rutherford, D. T.; Christie, S. D. R.
Tetrahedron Lett. 2000, 41, 1255–1259; (b) Maishal, T.
K.; Sinha-Mahapatra, D. K.; Paranjape, K.; Sarkar, A.
Tetrahedron Lett. 2002, 43, 2263–2267.
18. Related dihydrofurans have also been prepared by enzy-
matic resolution. See: Schieweck, F.; Altenbach, H. J.
Tetrahedron: Asymmetry 1998, 9, 403–406.
Financial support by DGESIC PB98-1510 (Ministerio
de Educacio´n y Cultura, Spain) is acknowledged. S.A.
and F.B. thank CIRIT (Generalitat de Catalunya) for a
grant. Technical assistance by the Servei de Recursos
Cientifics (URV) is acknowledged.
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