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J Am Chem Soc. 2008 Nov 26;130(47):16031-7. doi: 10.1021/ja805780u.

Solid-phase synthesis of stereoregular oligodeoxyribonucleoside phosphorothioates using bicyclic oxazaphospholidine derivatives as monomer units.

Author information

1
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Bioscience Building 702, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan.

Abstract

Nucleoside 3'-O-bicylic oxazaphospholidine derivatives were designed as monomer units for a solid-phase synthesis of stereoregular oligodeoxyribonucleoside phosphorothioates (PS-ODNs). The trans-isomers of appropriately designed nucleoside 3'-O-bicyclic oxazaphospholidine derivatives were generated exclusively by the reaction between the 3'-OH of the corresponding protected nucleosides and 2-chloro-1,3,2-oxazaphospholidine derivatives. The resultant trans-oxazaphospholidine isomers were configurationally stable, and their diastereopurity was not impaired by epimerization in the presence of an acidic activator during the condensation on a solid support. As a result, the formation of both (Rp)- and (Sp)-phosphorothioate internucleotide linkages by using the oxazaphospholidine monomers and the acidic activator proceeded without any loss of diastereopurity (diastereoselectivity > or = 99:1). In addition, ab initio molecular orbital calculations showed that the epimerization of oxazaphospholidine derivatives was most likely to proceed via an edge inversion process that was accelerated by N-protonation. The calculations rationalized not only the relations between the ring structure and the configurational stability of the oxazaphospholidines observed in this study but also the observations reported in the literature that the inversion of tricoordinated organophosphorus compounds were accelerated by acids or nucleophiles.

PMID:
18980312
DOI:
10.1021/ja805780u
[Indexed for MEDLINE]

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