Nucleoside H-Phosphonates. 18. Synthesis of Unprotected Nucleoside 5‘-H-Phosphonates and Nucleoside 5‘-H-Phosphonothioates and Their Conversion into the 5‘-Phosphorothioate and 5‘-Phosphorodithioate Monoesters

Abstract

A simple and efficient protocol for the preparation of unprotected nucleoside 5′-H-phosphonates and nucleoside 5′-H-phosphonothioates via a one-step deprotection of suitable precursors with methylamine has been developed. The synthetic utility of the unprotected nucleotide derivatives was demonstrated by converting them under mild conditions to the corresponding nucleoside 5′phosphorothioate and nucleoside 5′-phosphorodithioate monoesters. Factors affecting oxidation of H-phosphonate, H-phosphonothioate, and phosphite derivatives with elemental sulfur are also discussed.

α‐d‐Glucofuranose and α‐d‐allofuranose diacetonides and silyl ether of α‐d‐glucofuranose diacetonide in dithiophosphorylation reactions

“…Carbohydrate phosphates have been the subject of study of nucleosides and their prodrugs with improved cellular permeability and antiviral or anticancer activities . Monothiophosphorylated and dithiophosphorylated carbohydrates were also obtained . Meanwhile, due to their chirality at the phosphorus center and higher stability toward enzymatic hydrolysis, phosphorothioate derivatives have proven to be valuable as model constructs for designing enzyme‐catalyzed phosphoryl transfer reactions .…”

“…Monothiophosphorylated and dithiophosphorylated carbohydrates were also obtained . Meanwhile, due to their chirality at the phosphorus center and higher stability toward enzymatic hydrolysis, phosphorothioate derivatives have proven to be valuable as model constructs for designing enzyme‐catalyzed phosphoryl transfer reactions . Common methods of synthesizing monothiophosphorylated and dithiophosphorylated carbohydrates are usually based on the reaction of phosphorothioic acids with sugar oxiranes, photochemical addition of diethyl thiophosphonate to unsaturated sugars, reaction of unprotected nucleosides with 2‐( N , N′ ‐di‐ iso ‐propylamino)‐1,3,2‐oxathiaphospholane in the presence of 1 H ‐tetrazole followed by sulfurization with Beaucage's reagent, reaction of O ‐acetyl protected thymine, cytosine, adenine, or guanine nucleosides with 2‐( N,N′ ‐di‐ iso ‐propylamino)‐ or 2‐chloro‐1,3,2‐oxathiaphospholanes followed by sulfurization with elemental sulfur, or reaction of nucleoside H ‐phosphonate monoesters with hydrogen sulfide in the presence of pivaloyl chloride .…”

“…Thus, O ‐acyl protection of hydroxyl groups is usually used to obtain nucleoside dithiophosphates and trithiophosphates . Isopropylidene moiety have been reported to be a more efficient protecting group to prepare α‐ d ‐glucofuranose and α‐ d ‐allofuranose dithiophosphates and their nucleotide derivatives …”

1,2:5,6-Di-O-Cyclohexylidene-d-Mannitol and Its Bis(Trimethylsilyl) Ether in the Dithiophosphorylation Reactions

“…Monothio‐ and dithiophosphorylated monosaccharides possess the chiral phosphorus center and stability toward enzymatic hydrolysis. They have usually prepared by the reactions of phosphorothioic acids with sugar oxiranes or phosphorus reagents with monosaccharides followed by sulfurization with elemental sulfur or with hydrogen sulfide . The synthetic dithiophosphoryl derivatives of monosaccharides seem to possess potential selective antibacterial activity and lower toxicity to warm‐blooded animals.…”

Silylation‐Mediated Transesterification of O‐Phenyl H‐Phosphonothioates − A New Entry to Nucleoside H‐Phosphonothioate Monoesters

“…Due to their higher stability, ease of handling, and efficiency in solid-phase synthesis, [6Ϫ8] H-phosphonothioate building blocks [1,9] seem to be superior to phosphorothioamidite derivatives [10] in the synthesis of nucleotide analogues with multiple modifications at the phosphorus centre that are difficult to prepare in other ways, for example from nucleoside phosphorodithioates, [6,7,11,12] nucleoside phosphoramidothioates, [13] nucleoside phosphorofluoridothioates, [14] etc. Despite their usefulness in the synthesis of various types of phosphorus compounds, there are only a handful of synthetic methods available for the preparation of nucleoside H-phosphonothioate monoesters.…”