The Case for the Intermediacy of Monomeric Metaphosphate Analogues during Oxidation of H-Phosphonothioate, H-Phosphonodithioate, and H-Phosphonoselenoate Monoesters: Mechanistic and Synthetic Studies

Abstract

Studies on the reaction of H-phosphonothioate, H-phosphonodithioate, and H-phosphonoselenoate monoesters with iodine in the presence of a base led to identification of a unique oxidation pathway, which consists of the initial oxidation of the sulfur or selenium atom in these compounds, followed by oxidative elimination of hydrogen iodide to generate the corresponding metaphosphate analogues. The intermediacy of the latter species during oxidation of the investigated H-phosphonate monoester derivatives with iodine was supported by various diagnostic experiments. The scope and limitation of these oxidative transformations for the purpose of the synthesis of nucleoside phosphorothioate, nucleoside phosphorodithioate, and nucleoside phosphoroselenoate diesters was also investigated.

Solid-Phase Synthesis of Phosphorothioate/Phosphonothioate and Phosphoramidate/Phosphonamidate Oligonucleotides

“…The use of 0.1 M iodine in pyridine-methanol (50:50) mixture led to only 80% yield of the expected MeO-P (V) product. However, Atherton-Todd reaction [14,15,16] conditions (CCl 4 -pyridine-methanol) provided an acceptable 95% yield of MeO-P (V) product. Moreover, no hydrolysis of internucleotide linkage was observed.…”

Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization

“…These products were immediately hydrolyzed by addition of approximately 2 equiv of aqueous triethylammonium bicarbonate (TEAB) to give the H -phosphonate 16 . Treatment of 16 with approximately 4 equiv of phenylacetyl disulfide (PADS) [ 57 ] gave the known dinucleoside phosphorothioate 17 [ 26 , 58 ].…”

Solid‐Phase Synthesis of Oligonucleotide 5′‐(α‐P‐Thio)triphosphates and 5′‐(α‐P‐Thio)(β,γ‐methylene)triphosphates

“…Unfortunately, these conditions could not be applied, as CCl 4 cannot efficiently oxidize H-phosphonothioate, whereas other oxidants such as iodine, bromine, and different carbon tetrahalides are successful. [11] Small aliquots of the solid-supported 5Ј-Hp S T 6 were treated with several solutions mixing imidazole, triethylamine with CBr 4 , or iodine in different solvents such as pyridine, acetonitrile, or THF. After removal of the oxidative solution and after washing the support, a 0.25 m pyrophosphate solution in DMF was applied to the synthesis column for 18 h. Then, ammonia treatment released and deprotected the ON from the solid support.…”