title: Synthesis of nucleoside boranophosphoramidate prodrugs conjugated with amino acids.
abstract: [structure: see text] Nucleoside boranophosphates and nucleoside amino acid phosphoramidates have been shown to be potent antiviral and anticancer agents with the potential to act as nucleoside prodrugs. A combination of these two types of compounds results in a boranophosphoramidate linkage between the nucleoside and amino acid. This new class of potential prodrugs is expected to possess advantages conferred by both types of parent compounds. Two approaches, specifically the H-phosphonate and oxathiaphospholane approaches, are described here to synthesize nucleoside boranophosphoramidate prodrugs conjugated with amino acids. The H-phosphonate approach involves a key intermediate, silylated nucleoside amino acid phosphoramidite 6, prepared from a series of reactions starting from nucleoside H-phosphonate in the presence of condensing reagent DPCP. Due to the lengthy procedure and the difficulties in removing DPCP from the final products, we switched to the oxathiaphospholane approach in which the DBU-assisted oxathiaphospholane ring-opening process constituted a key step for the generation of nucleoside amino acid boranophosphoramidates 24. We demonstrate that this key step did not cause any measurable C-racemization of boranophosphorylated amino acids 22. Diastereomers of compounds 24a-f were separated by RP-HPLC. An "adjacent"-type mechanism is proposed to explain the diastereomer ratio in the final products obtained via the oxathiaphospholane approach. A tentative assignment of configuration for the diastereomers was carried out based on the mechanism, molecular modeling, and (1)H NMR. Conclusively, the oxathiaphospholane methodology proved to be more facile and efficient than H-phosphonate chemistry in the preparation of the nucleoside amino acid boranophosphoramidate analogues that are promising as a new type of antiviral prodrugs.
authors.affiliation: Department of Chemistry, Box 90346, Duke University, Durham, North Carolina 27708-0346, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Barbara Ramsay
authors.initials: BR
authors.lastname: Shaw
mesh_terms: D000577:Amides / Q000138:chemical synthesis*; D000596:Amino Acids / Q000737:chemistry*; D001896:Boron Compounds / Q000138:chemical synthesis*; D015195:Drug Design; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry*; D010756:Phosphoric Acids / Q000138:chemical synthesis*; D011355:Prodrugs / Q000138:chemical synthesis*
chemical_list: D000577:Amides; D000596:Amino Acids; D001896:Boron Compounds; D009705:Nucleosides; D010756:Phosphoric Acids; D011355:Prodrugs; C011067:phosphoramidic acid