Utility of bis(N,N-dialkylamino) methoxyphosphine as a new class of phosphitylating agent for oligonucleotide synthesis

Abstract

The phosphite triester method is known to be effective for the synthesis of oligonucleotides, especially in the solid phase system. This approach involves the reaction of a suitably protected nucleoside, a bifunctional phosphitylating agent of methoxydichlorophosphine or nucleoside phosphoramidites, and second protected nucleoside. Mild oxidation by iodine-water generates the natural internucleotide phosphate bond. A serious limitation of this methodology, however, has been the instability of the phosphitylating agents. Conventional phosphitylating agents such as nucleoside phosphoramidites, monotetrazolides, or phosphomonochloridites are found to be very unstable toward hydrolysis and air oxidation. In our case, we have solved this problem by introducing a new class of phosphitylating agent. Bis-(N,N-dialkylamino)methoxyphosphine showed a reasonable stability under normal laboratory conditions to hydrolysis and air oxidation, and could be activated effectively by treating with several heterocyclic amines such as imidazole, triazole and tetrazole. This thesis outlines the synthesis of this new phosphitylating agent, its characterization and its reactivity toward deoxyoligonucleotide synthesis.