P-stereocontrolled synthesis of oligo(nucleoside N3'→O5' phosphoramidothioate)s - opportunities and limitations.

3'- N -(2-Thio-1,3,2-oxathiaphospholane) derivatives of 5'- O -DMT-3'-amino-2',3'-dideoxy-ribonucleosides ( N OTP-N), that bear a 4,4-unsubstituted, 4,4-dimethyl, or 4,4-pentamethylene substituted oxathiaphospholane ring, were synthesized. Within these three series, N OTP-N differed by canonical nucleobases ( i.e. , Ade Bz , Cyt Bz , Gua iBu , or Thy). The monomers were chromatographically separated into P-diastereomers, which were further used to prepare N NPS N' dinucleotides (3), as well as short P-stereodefined oligo(deoxyribonucleoside N3'→O5' phosphoramidothioate)s (NPS-) and chimeric NPS/PO- and NPS/PS-oligomers. The condensation reaction for N OTP-N monomers was found to be 5-6 times slower than the analogous OTP derivatives. When the 5'-end nucleoside of a growing oligomer adopts a C3'- endo conformation, a conformational 'clash' with the incoming N OTP-N monomer takes place, which is a main factor decreasing the repetitive yield of chain elongation. Although both isomers of N NPS N' were digested by the HINT1 phosphoramidase enzyme, the isomers hydrolyzed at a faster rate were tentatively assigned the R P absolute configuration. This assignment is supported by X-ray analysis of the protected dinucleotide DMT dG iBu NPSMe T OAc , which is P-stereoequivalent to the hydrolyzed faster P-diastereomer of dG NPS T.