7170
T. Santhosh Kumar et al. / Tetrahedron Letters 49 (2008) 7168–7170
donor21 in concert with 20% Pd(OH)2/C as catalyst and THF/MeOH
(9:1, v/v) as reaction solvent, in addition to desired diol 6, only re-
sulted in traces of the reduced nucleoside 7 in the crude. After sep-
aration of 7 during column chromatography, desired LNA uracil
diol 6 was afforded in 91% yield, pure by 1H NMR.17 In fact, the ura-
cil moiety of 6 proved highly stable to these hydrogenation condi-
tions as excess formic acid (up to 13 equiv) and prolonged reaction
times (up to 22 h) did never result in more than 2% formation of
the reduced product. The problematic susceptibility of the C5–C6
double bond of pyrimidine nucleobases to undergo reduction dur-
ing hydrogenation conditions has been noted.8b,22 To our knowl-
edge, the presented results describe the first use of catalytic
transfer hydrogenation conditions with formic acid to avoid nucle-
obase reduction, and warrant further investigations of these condi-
tions for applications in nucleoside chemistry.
2. For reviews see: (a) Meldgaard, M.; Wengel, J. J. Chem. Soc., Perkin Trans. 1 2000,
3539–3554; (b) Leumann, C. J. Bioorg. Med. Chem. 2002, 10, 841–854.
3. For selected recent examples see: (a) Albꢀk, N.; Petersen, M.; Nielsen, P. J. Org.
Chem. 2006, 71, 7731–7740; (b) Honcharenko, D.; Vargese, O. P.; Plashkevych,
O.; Barman, J.; Chattopadhyaya, J. J. Org. Chem. 2006, 71, 299–314; (c) Varghese,
O. P.; Barman, J.; Pathmasiri, W.; Plaskevych, O.; Honcharenko, D.;
Chattopadhyaya, J. J. Am. Chem. Soc. 2006, 128, 15173–15187; (d) Hari, Y.;
Obika, S.; Ohnishi, R.; Eguchi, K.; Osaki, T.; Ohishi, H.; Imanishi, T. Bioorg. Med.
Chem. 2006, 14, 1029–1038; (e) Srivastava, P.; Barman, J.; Pathmasiri, W.;
Plaskevych, O.; Wenska, M.; Chattopadhyaya, J. J. Am. Chem. Soc. 2007, 129,
8362–8379; (f) Swayze, E. E.; Seth, P. P. Isis Pharmaceuticals WO 2007/090071;
(g) Rahman, S. M. A.; Seki, S.; Obika, S.; Yoshikawa, H.; Miyashita, K.; Imanishi,
T. J. Am. Chem. Soc. 2008, 130, 4886–4896.
4. Koshkin, A. A.; Singh, S. K.; Nielson, P.; Rajwanshi, V. K.; Kumar, R.; Meldgaard,
M.; Olsen, C. E.; Wengel, J. Tetrahedron 1998, 54, 3607–3630.
5. Obika, S.; Nanbu, D.; Hari, Y.; Andoh, J.; Morio, K.; Doi, T.; Imanishi, T.
Tetrahedron Lett. 1998, 39, 5401–5404.
6.
a
-
L-LNA: Sørensen, M. D.; Kv
ꢀrnø, L.; Bryld, T.; Håkansson, A. E.; Verbeure, B.;
Gaubert, G.; Herdewijn, P.; Wengel, J. J. Am. Chem. Soc. 2002, 124, 2164–2176.
7. 20-Amino-LNA selected examples: (a) Sørensen, M. D.; Petersen, M.; Wengel, J.
Chem. Commun. 2003, 2130–2131; (b) Hrdlicka, P. J.; Babu, B. R.; Sørensen, M.
D.; Wengel, J. Chem. Commun. 2004, 1478–1479; (c) Hrdlicka, P. J.; Babu, B. R.;
Sørensen, M. D.; Harrit, N.; Wengel, J. J. Am. Chem. Soc. 2005, 127, 13293–
13299; (d) Kalek, M.; Madsen, A. S.; Wengel, J. J. Am. Chem. Soc. 2007, 129,
9392–9400; (e) Umemoto, T.; Hrdlicka, P. J.; Babu, B. R.; Wengel, J.
ChemBioChem 2007, 8, 2240–2248.
To sum up, a short, high yielding and very practical synthesis of
LNA uracil diol 6 has been developed from the easily accessible gly-
cosyl donor 1.14,15 Diol 6 can ultimately be obtained from commer-
cially available diacetone-
a
-D
-allose in ꢀ52% yield, and remarkably
only necessitates two chromatographic purification steps. Thus,
the developed route toward 6 represents a significant improve-
ment in overall yield and convenience compared to existing
routes4,12 and works reliably on larger scale synthesis (ꢀ10 g). Fac-
ile access to 6 will allow full exploration of RNA-based LNA-tech-
nology applications11b,d as it: (1) is easily converted to the
corresponding phosphoramidite building block LNA-U over two
steps (Scheme 1)4,12 for automated incorporation into ONs, and/
or (2) could be converted to the corresponding 50-triphosphates
and used in enzyme-catalyzed synthesis of LNA-U-modified RNA-
strands for generation of aptamers via SELEX.23
8. 20-Amino-
a-L-LNA selected examples: (a) Hrdlicka, P. J.; Kumar, T. S.; Wengel, J.
Chem. Commun. 2005, 4279–4281; (b) Kumar, T. S.; Madsen, A. S.; Wengel, J.;
Hrdlicka, P. J. J. Org. Chem. 2006, 71, 4188–4201; (c) Kumar, T. S.; Wengel, J.;
Hrdlicka, P. J. ChemBioChem 2007, 8, 1122–1125; (d) Kumar, T. S.; Madsen, A. S.;
Wengel, J.; Hrdlicka, P. J. Nucleosides Nucleotides Nucleic Acids 2007, 26, 1403–
1405; (e) Andersen, N. K.; Wengel, J.; Hrdlicka, P. J. Nucleosides Nucleotides
Nucleic Acids 2007, 26, 1415–1417; (f) Kumar, T. S.; Madsen, A. S.; Østergaard,
M. E.; Wengel, J.; Hrdlicka, P. J. J. Org. Chem. 2008, 73, 7060–7066.
9. (a) Petersen, M.; Wengel, J. Trends Biotechnol. 2003, 21, 74–81; (b) Kaur, H.;
Babu, B. R.; Maiti, S. Chem. Rev. 2007, 107, 4672–4697.
10. (a) Wienholds, E.; Kloosterman, W. P.; Misk, E.; Alvarez-Saavedra, E.; Berezikov,
E.; de Brujin, E.; Horwitz, H. R.; Kauppinen, S.; Plasterk, R. H. A. Science 2005,
309, 310–311; (b) Frieden, M.; Ørum, H. IDrugs 2006, 9, 706–711; (c)
Grünweller, A.; Hartmann, R. K. Biodrugs 2007, 21, 235–243.
11. (a) Seferos, D. S.; Giljohann, D. A.; Rosi, N. L.; Mirkin, C. A. ChemBioChem 2007,
8, 1230–1232; (b) Bramsen, J. B.; Laursen, M. B.; Damgaard, C. K.; Lena, S. W.;
Babu, B. R.; Wengel, J.; Kjems, J. Nucleic Acids Res. 2007, 35, 5886–5897; (c)
McKenzie, F.; Faulds, K.; Graham, D. Chem. Commun. 2008, 2367–2369; (d)
Veedu, R. N.; Vester, B.; Wengel, J. J. Am. Chem. Soc. 2008, 136, 8124–8125.
12. Obika, S.; Uneda, T.; Sugimoto, T.; Nanbu, D.; Minami, T.; Doi, T.; Imanishi, T.
Bioorg. Med. Chem. 2001, 9, 1001–1011.
13. Koshkin, A. A.; Rajwanshi, V. K.; Wengel, J. Tetrahedron Lett. 1998, 39, 4381–
4384.
14. Pfundheller, H. M.; Lomholt, C. Curr. Protoc. Nucleic Acid Chem. 2002, 4.12.1–
4.12.16.
Acknowledgments
We greatly appreciate financial support from Idaho NSF EPSCoR,
the BANTech Center at the University of Idaho, a University of Ida-
ho Research Office and Research Council Seed Grant, and the Dan-
ish Research Agency.
15. Koshkin, A. A.; Fensholdt, J.; Pfundheller, H. M.; Lomholt, C. J. Org. Chem. 2001,
66, 8504–8512.
Supplementary data
16. Rosenbohm, C.; Christensen, S. M.; Sørensen, M. D.; Pedersen, D. S.; Larsen,
L.-E.; Wengel, J.; Koch, T. Org. Biomol. Chem. 2003, 1, 655–663.
17. See Supplementary data.
18. Matteson, D. S.; Man, H.; Ho, O. C. J. Am. Chem. Soc. 1996, 118, 4560–4566.
19. Sajiki, H.; Kuno, H.; Hirota, K. Tetrahedron Lett. 1997, 38, 399–402.
20. Bieg, T.; Szeja, W. Synthesis 1985, 1, 76–77.
General experimental section, experimental description, and
characterization data of compounds 2–6, copies of 1H, 13C NMR,
1H–1H COSY, and/or 1H–13C HSQC spectra of 2–6. Supplementary
data associated with this article can be found, in the online version,
21. ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G. E. J. Org. Chem. 1979,
44, 3442–3444.
22. (a) Watkins, B. E.; Kiely, J. S.; Rapoport, H. J. Am. Chem. Soc. 1982, 104, 5702–
5708; (b) Pedersen, D. S.; Koch, T. Synthesis 2004, 578–582; (c) Johnson, D. C.;
Widlanski, T. S. Org. Lett. 2004, 6, 4643–4646; (d) Jin, S.; Miduturu, C. V.;
McKinney, D. C.; Silverman, S. K. J. Org. Chem. 2005, 70, 4284–4299.
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References and notes
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