Second Generation Synthesis of Modified Dinucleotide Analogues Featuring a Difluorophosphin(othio)yl Linkage

Abstract

AbstractA second generation route to protected modified dinucleotides encompassing a difluorophosphinothioyl unit in replacement of the phosphoryl diester is described. It relies on (i) the preparation of 6’‐iodonucleosides, (ii) their coupling with a furanosyl 3’‐difluoromethyl H‐phosphinothioate, and (iii) the introduction of the second nucleobase. Thus, a short and high yielding preparation of 6’‐iodonucleosides from commercially available materials is reported, and their coupling reaction with a furanosyl 3’‐difluoromethyl H‐phosphinothioate satisfactorily delivered the desired protected bisfuranosyl derivatives featuring both a difluorophosphinothioyl unit and a nucleobase unambiguously installed on the anomeric position of the bottom furanose. Introduction of the second nucleobase generated the desired heterodinucleotides in low yields. Careful analysis of the materials indicates that the classical Vorbrüggen conditions may induce the trans‐N‐glycosylation process to take place, resulting in the competitive replacement of a nucleobase with another one, thereby generating mixtures of homo‐ and heterodinucleotides.