Towards the stereoselective synthesis of oligonucleotide phosphorothioates and phosphonate derivatives

Chiral auxiliary 1,2-di-O-isopropylidene-3-C-cyanoethyl-5-deoxy-5-isopropylamino-D-xylofuranose 3-32 was synthesized. Cyclic phosphoramidite 3-34 derived from 3-32 is a useful precursor for the stereoselective synthesis of phosphorothioate. The chiral auxiliary can be easily removed at the end of the synthesis by treatment with concentrated ammonia. The major dithymidine phosphorothioate isomer with a SP configuration was obtained.The allyl group was investigated as a protecting group for the internucleotide linkage. The removal of the allyl group in dimer 4-6S or 4-6O was achieved by treatment with nucleophiles. Solid phase study indicated this to be a general method for the routine solid phase synthesis of oligonucleotide phosphorothioates and phosphates.*A new type of chiral auxiliary 5-20 which incorporates indole and imidazole moieties was synthesized. It led to the stereoselective synthesis of a novel indolophosphorothioate 5-37 with 90% de and the formation of an alkylphosphinate analog 5-41 as a single diastereomer.Chiral indolo-oxazaphosphorine 6-22 was prepared from L-tryptophan. Dithymidine phosphorothioate with ≥95% de was obtained while using 6-22 as a precursor. The removal of the chiral auxiliary was achieved by heating in concentrated ammonia at 55ºC for 16 hours. The indolo-oxazaphosphorines derived from L- or D-tryptophans led to the formations of dithymidine phosphorothioates with RP or SP configurations, respectively. The methodology was applied successfully to the solid phase synthesis of phosphorothioate dimers.**Please refer to dissertation for diagrams