Nueleoside Oxazaphospholidines as Novel Synthons in Oligonucleotide Synthesis

摘要

Since the introduction in 1981 of the nucleoside phos-phoramidite synthons by Beaucage and Caruthers and the subsequent refinement of this pioneering chemistry, the synthesis of oligonucleotides for routine applications in molecular biology and in diagnostics, as well as for the large-scale manufacture of modified oligonucleotides for antisense-based therapeutic applications, has been greatly facilitated. In this context, the beta-cyanoethyl phosphoramidite nucleoside phosphoramidite 1 is the most widely used synthon. We considered the possibilityof using nucleoside oxazaphospholidines having the general structure 2, readily derived from the corresponding beta-amino alcohols, as alternative synthons. Our interest in nucleoside oxazaphospholidines was spurred by the availability of vast chiral pools of famine alcohols, the expectation being that the substituents in the chiral bxazaphospholidine ring can effect diastereofacial selectivity in internucleotidic coupling reactions. Our ongoing efforts in this latter area, as applied to the synthesis of oligonucleoside phosphorothioates, have been presented elsewhere in a preliminary paper. In the present work, we demonstrate the generality in the use of simple nucleoside phosphoramidite synthons; such as 3-methyl-1,3,2-oxazaphospholidines 3—6, in the synthesis of oli-godeoxynucleotides.