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.