-Stereodefined phosphorothioate analogs of glycol nucleic acids-synthesis and structural properties.

Enantiomerically pure, protected acyclic nucleosides of the GNA type (glycol nucleic acids) (N'), obtained from ()-(+)- and ()-(-)-glycidols and the four canonical DNA nucleobases (Ade, Cyt, Gua and Thy), were transformed into 3'--DMT-protected 2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane derivatives (OTP-N') containing a second stereogenic center at the phosphorus atom. These monomers were chromatographically separated into -diastereoisomers, which were further used for the synthesis of -stereodefined "dinucleoside" phosphorothioates NT (N = A, C, G, T). The absolute configuration at the phosphorus atom for all eight NT was established enzymatically and verified chemically, and correlated with chromatographic mobility of the OTP-N' monomers on silica gel. The N units (derived from ()-(+)-glycidol) were introduced into self-complementary PS-(DNA/GNA) octamers of preselected, uniform absolute configuration at P-atoms. Thermal dissociation experiments showed that the thermodynamic stability of the duplexes depends on the stereochemistry of the phosphorus centers and relative arrangement of the N units in the oligonucleotide strands. These results correlate with the changes of conformation assessed from circular dichroism spectra.