literature survey revealed that it usually required lengthy steps
and high-cost starting materials, such as unnatural carbohydrates,
and the overall yields were often unsatisfactory. Improved
syntheses of 4-thiofuranoses of L-arabino,5 2-deoxy-D-ribo,6 and
D-galacto7 configurations have appeared in recent years; how-
ever, the practical synthesis of 4-thio-D-ribofuranose (2) still
remains a challenge, and this has presumably impeded the
development of 4′-thioribonucleosides. To our knowledge, there
are only a handful of syntheses of 2 and its derivatives, all
starting from costly L-lyxose.4,8 As an alternative, Matsuda9 and
Yoshimura10 recently published elegant new protocols for the
synthesis of 4′-thioribonucleosides via the Pummerer reaction.11
In view that the thioglycosylation of the 4-thioribofuranose
scaffold usually proceeded with useful to good â-selectivity,8b,12
we felt that an efficient preparation of 2 and its peracyl
derivatives would suffice to make 4′-â-thioribonucleosides more
accessible. Further elaboration at C2 after appropriate protection
of 3,5-hydroxyls could also be explored to afford valuable
synthetic precursors to 2′-modified 4′-thionucleosides possessing
potent biological activities, for example, 4′-thioFAC (3) and
4′-thioDMDC (4).1e Herein we wish to report a concise and
practical synthesis of derivatives of 2 starting from cheap
D-glucose derivative 5.
We envisioned that the C2-C6 portion of D-glucose could
be utilized as the carbon skeleton in our target molecule after
adjustment of the stereochemistry of C3 and C5, whereas C1
was to be taken off by oxidative cleavage of vicinal diol (Figure
1). Inversion at C3 of glucose is routine, thus the key to the
above strategy is the introduction of sulfur with retention of
configuration at C5,13 which has received little attention and
its synthetic utility for thiosugars is not fully appreciated yet.
Initially, a synthetic route adapted from Yoshimura’s im-
proved synthesis of 4′-thioFAC was probed1f (Scheme 1). 1,2:
5,6-Di-O-isopropylidene-R-D-allofuranose (6) was easily pre-
pared from the corresponding D-glucose derivative (5) in two
steps.14 Benzoylation, selective deprotection of the 5,6-isopro-
A Facile and Practical Synthesis of Peracylated
4-Thio-D-ribofuranoses from D-Glucose
Zhi-Hua Sun and Bing Wang*
Department of Chemistry, Fudan UniVersity, 220 Handan Road,
Shanghai 200433, China
ReceiVed December 14, 2007
A practical synthesis of a peracylated 4-thio-D-ribofuranose
14 starting from inexpensive D-glucose is described. The
C2-C6 portion of D-glucose was utilized, in which sulfur
was introduced to C5 in two consecutive displacement
reactions with net retention of configuration under mild
conditions.
In the search for effective antiviral and antitumor agents,
nucleosides are among the most prominent and promising
candidates. Over the past 15 years, 4′-thionucleosides (1), in
which the lactol ring oxygen is replaced by a sulfur atom, have
attracted much attention due to their potent biological activity1
and unique metabolic stability.1a,2 Furthermore, certain 4′-
thionucleosides, when incorporated into RNA strands, lead to
enhanced thermal stability of the resulting modified RNA
duplex.3 As the parent building block for 4′-thionucleosides,
4-thiopentofuranoses have been the subject of many synthetic
efforts since the pioneering work of Reist and Whistler.4 A
(5) For examples, see: (a) Whistler, R. L.; Nayak, U. G.; Perkins, A.
W., Jr. Chem. Commun. 1968, 1339. (b) Whistler, R. L.; Nayak, U. G.;
Perkins, A. W., Jr. J. Org. Chem. 1970, 35, 519. (c) Jeong, L. S.; Moon,
H. R.; Choi, Y. J.; Chun, M. W.; Kim, H. O. J. Org. Chem. 1998, 63,
4821. (d) Satoh, H.; Yoshimura, Y.; Sakata, S.; Miura, S.; Machida, H.
Bioorg. Med. Chem. Lett. 1998, 8, 989. (e) Wirsching, J.; Voss, J. Eur. J.
Org. Chem. 1999, 691.
(6) Fu, Y.-L.; Bobek, M. J. Org. Chem. 1976, 41, 3831.
(7) Varela, O.; Cicero, D.; de Lederkremer, R. M. J. Org. Chem. 1989,
54, 1884.
(1) For examples, see: (a) Dyson, M. R.; Coe, P. L.; Walker, R. T. J.
Med. Chem. 1991, 34, 2782. (b) Secrist, J. A., III; Tiwari, K. N.; Riordan,
J. M.; Montgomery, J. A. J. Med. Chem. 1991, 34, 2361. (c) Bellon, L.;
Barascut, J. L.; Imbach, J. L. Nucleosides Nucleotides 1992, 11, 1467. (d)
Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata,
S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1996, 61, 822. (e) Yoshimura,
Y.; Kitano, K.; Yamada, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata,
S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1997, 62, 3140. (f) Yoshimura,
Y.; Endo, M.; Muira, S.; Sakata, S. J. Org. Chem. 1999, 64, 7912 and
references cited therein.
(8) (a) Urbas, B.; Whistler, R. L. J. Org. Chem. 1966, 31, 813. (b)
Haeberli, P.; Berger, I.; Pallen, P. S.; Egli, M. Nucleic Acids Res. 2005,
33, 3965.
(2) (a) Parks, R. E., Jr.; Stoeckler, J. D.; Cambor, C.; Savarese, T. M.;
Crabtree, G. W.; Chu, S.-H. In Molecular Actions and Targets for Cancer
Chemotherapeutic Agents; Sartorelli, A. C., Lazo, J. S., Bertino, J. R., Eds.;
Academic Press: New York, 1981; p 229. (b) Rahim, S. G.; Littler, E.;
Powell, K. L.; Collins, P. L.; Dyson, M. R.; Walker, R. T. Proceedings of
the 31st ICAAC; Chicago, 1991; p 1232.
(3) (a) Leydier, C.; Bellon, L.; Barascut, J. L.; Morvan, F.; Rayner, B.;
Imbach, J. L. Antisense Res. DeV. 1995, 5, 167. (b) Leydier, C.; Bellon, L.;
Barascut, J. L.; Imbach, J. L. Nucleosides Nucleotides 1995, 14, 1027. (c)
Boggon, T. J.; Hancox, E. L.; McAuley-Hecht, K. E.; Connolly, B. A.;
Hunter, W. N.; Brown, T.; Walker, R. T.; Leonard, G. A. Nucleic Acids
Res. 1996, 24, 951. (d) Jones, G. D.; Altmann, K.-H.; Husken, D.; Walker,
R. T. Bioorg. Med. Chem. Lett. 1997, 7, 1275.
(9) Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A. J. Am.
Chem. Soc. 2000, 122, 7233.
(10) Yoshimura, Y.; Kuze, T.; Ueno, M.; Komiya, F.; Haraguchi, K.;
Tanaka, H.; Kano, F.; Yamada, K.; Asami, K.; Kaneko, N.; Takahata, H.
Tetrahedron Lett. 2006, 47, 591.
(11) (a) Kita, Y.; Yasuda, H.; Tamura, O.; Itoh, F.; Tamura, Y.
Tetrahedron Lett. 1984, 25, 4681. (b) Kita, Y.; Tamura, O.; Yasuda, H.;
Itoh, F.; Tamura, Y. Chem. Pharm. Bull. 1985, 33, 4235.
(12) (a) Whistler, R. L.; Doner, L. W.; Nayak, U. G. J. Org. Chem. 1971,
36, 108. (b) Bobek, M.; Bloch, A.; Parthasarathy, R.; Whistler, R. L. J.
Med. Chem. 1975, 18, 784.
(13) For simple inversion of C5 configuration by sulfur nucleophiles,
see: Calvo-Flores, F. G.; Garc´ıa-Mendoza, P.; Herna´ndez-Mateo, F.; Isac-
Garc´ıa, J.; Santoyo-Gonza´lez, F. J. Org. Chem. 1997, 62, 3944 and
references cited therein.
(4) (a) Reist, E. J.; Gueffroy, D. E.; Goodman, L. J. Am. Chem. Soc.
1964, 86, 5658. (b) Whistler, R. L.; Dick, W. E.; Ingle, T. R.; Rowell, R.
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10.1021/jo7026596 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/20/2008
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J. Org. Chem. 2008, 73, 2462-2465