Studies on Stereospecific Formation of P -Chiral Internucleotide Linkage: Synthesis of all- Rp and all- Sp Methylphosphonate Pentanucleotide d(MMTrA PMe T PMe T PMe C PMe TAc) via Grignard Activated Coupling

Abstract

Synthesis of stereoregular 3‵,5‵-protected all-Rp and all-Sp methylphosphonate heterooligonucleotides d(MMTrA_PMeT_PMeT_PMeC_PMeTAc) (12) complementary to the fragment of HTV-1 splicing acceptor site was achieved via stereocontrolled formation of internucleotide linkage. The coupling was based on the transesterification of P-stereodefined monomer type of 5‵-O-monomethoxytrityl-2‵-O-deoxynucleoside 3‵-O-[O-(4-nitrophenyl)methylphosphonate]. The nucleophile was a t-butylmagnesium chloride activated 5‵-terniinal hydroxyl function of the growing olligonucleotide chain. This and other P-homochiral oligomers will be used as building blocks for the synthesis of biologically significant, longer stereoregular oligonucleotides.