Synthesis of bis(deoxyribonucleoside) phosphoromorpholidate derivatives for oligodeoxyribonucleotide preparation by use of a selective phosphitylating reagent.

概要

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Sequence-defined bis(deoxyribonucleoside) phosphoromorpholidate derivatives as stable intermediates to prepare oligodeoxyribonucleotides have been synthesized using morpholinodi(1-tetrazolyl)phosphine as a phosphitylating reagent. The general procedure is composed of following steps (in situ); a) a reaction of 5′-O-protected deoxyribonucleoside with morpholinodi(1-tetrazolyl)phosphine (phosphitylation), b) a reaction of the resulting 5′-O-protected deoxyribonucleoside phosphorobisamidite with the second deoxyribonucleoside (coupling), and c) a nonaqueous oxidation with <I>t</I>-BuOOH (oxidation). In the coupling step, the 5′-O-protected deoxyribonucleoside phosphorobisamidite was selectively reacted with 5′-OH group of the second deoxyribonucleoside, and therefore, a protection of hydroxyl groups of the second deoxyribonucleoside is not necessary. As the resulting P–N bond in the phosphoramidate linkage after oxidation is stable both in acidic and basic conditions, the morpholino function as a phosphoryl protecting group may have many potential use in the synthetic chemistry of oligonucleotide. A thymidine trimer can be obtained in a high yield by extending the present synthetic method.
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