Synthesis of analogues of oligonucleotides; synthesis of unprotected C-linked di- and tri-nucleotides

Abstract

The Wittig reaction between the N-benzyloxymethylthymidine-derived ylide 25 and the aldehyde 16 followed by hydrogenolysis gives access to the unprotected C-linked dinucleotide 20 on a multi-gram scale. Oxidation of the dinucleotide gives the aldehyde 27 which is condensed with the ylide 25 to give the unprotected bis-C-linked trinucleotide 29 after hydrogenolysis. The mono-C-linked trinucleotide 44 is prepared by oxidation of the dinucleotide ester 34 to the aldehyde 36 which is condensed with the ylide 25 followed by hydrogenolysis to give the mono-C-linked trinucleotide ester 38. This intermediate is also prepared from the C-linked dinucleotide 20 by conversion into the phosphoramidite 41 which is coupled with 3-acetylthymidine 15 to give the mono-C-linked trinucleotide phosphite 42. Oxidation and deprotection give the phosphate triester 38. Treatment of 38 with methanolic ammonia gives the fully unprotected mono-C-linked trinucleotide 44.

References

1. A. De Mesmaeker, R. Haner, P. Martin and H. E. Moser, Acc. Chem. Res., 1995, 28, 366; E. Uhlmann and A. Peyman, Chem. Rev., 1990, 90, 543; R. S. Varma, Synlett, 1993, 621.
2. K. Butterfield and E. J. Thomas, J. Chem. Soc., Perkin Trans. 1, 1998, 737.
3. K. Butterfield and E. J. Thomas, Synlett, 1993, 411.
4. C. K. Chu, B. Doboszewski, W. Schmidt, C. V. Ullas and P. Van Roey, J. Org. Chem., 1989, 54, 2767.
5. J. L. Van Aerschot, L. Jie and P. Herdewijn, Tetrahedron Lett., 1991, 32, 1905.
6. B. H. Lipshutz and J. J. Tegram, Tetrahedron Lett., 1980, 21, 3343.
7. J. Fiandor and S. Y. Tam, Tetrahedron Lett., 1990, 31, 597.
8. J. A. Montgomery and H. J. Thomas, J. Org. Chem., 1981, 46, 594.
9. K. E. Pfitzner and J. G. Moffatt, J. Am. Chem. Soc., 1965, 87, 5661.
10. A. D. Barone, J.-Y. Tang and M. H. Caruthers, Nucleic Acid Res., 1984, 12, 4051.
11. N. D. Sinha, J. Biernat, J. McManus and H. Koster, Nucleic Acid Res., 1984, 11, 4539.
12. J. Lebreton, A. De Mesmaeker and A. Waldner, Synlett, 1994, 54; S. Wendeborn, R. M. Wolf and A. De Mesmaeker, Tetrahedron Lett., 1995, 36, 6879.
13. G. R. Weihe and T. C. McMorris, J. Org. Chem., 1978, 43, 3942.