Synthesis of diastereomeric mixtures of 5'-C-hydroxymethylthymidine and introduction of a novel class of C-hydroxymethyl functionalised oligodeoxynucleotides.

Abstract

Novel 5'-C-hydroxymethyl substituted derivatives of thymidine have been prepared by dihydroxylation of the 5'C-methylene nucleoside 1. Osmium tetraoxide catalysed dihydroxylation of 1 afforded a 3:2 epimeric mixture of diols 2, whereas asymmetric dihydroxylation using AD-mix-alpha and AD-mix-beta resulted in mixtures 3 and 4 of the two epimeric diols, both enriched with the same diastereomer. Nucleosides 2 were transformed into phosphoramidites 8 which were used for solid phase synthesis of oligodeoxynucleotides (ODNs) containing 5'-C-(hydroxymethyl) functionalised thymidine monomers. This novel class of C-hydroxymethyl modified ODN-analogues exhibited promising affinity towards both complementary DNA and RNA as well as resistance towards 3'-exonucleolytic degradation.