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The stereospecific sulfurization of diribonucleoside H-phosphonate diesters with elemental sulfur (S8) provides the key reaction in the synthesis of four diastereomeric pairs of ribonucleoside phosphorothioates. The diesters are obtained by coupling properly protected uridine at its ribosyl methyl position to four protected ribonucleosides at their 4-ribosyl position with a phosphonate linkage. When exposed to the snake venom phosphodiesterase, only the Rp diastereomers undergo extensive hydrolysis while the Sp diastereomers prove resistant to the enzyme.

Two synthetic routes for the preparation of nucleoside selenophosphoramidates have been developed by using H-phosphonate derivatives as key substrates. The first method is a one-pot synthesis, which involves the condensation of an amine with H-phosphonate monoesters, mediated by a coupling agent, followed by oxidation with elemental selenium ( A ). The second approach makes use of the oxidative condensation reaction of H-phosphonoselenoate monoesters with amines promoted by iodine as an oxidizing agent ( B ). Both methods are efficient and experimentally simple, but the second method ( B ) seems to be more suited for the synthesis of selenophosphoramidates with bulky or sterically hindered amine residues. It has been shown that both methods also provide a convenient way to produce sulfurized counterparts, i.e., the corresponding thiophosphoramidate derivatives.

Boranephosphonate diesters react with heteroaromatic and certain tertiary amines in the presence of an oxidant (I 2 ) to afford the boron-modified phosphodiester analogues containing a P-B-N structural motif. Our multinuclear 31 P and 11 B NMR spectroscopy studies lend support for a two-step mechanism involving generation of a λ 3 -boranephosphonate intermediate that immediately coordinates an amine in the solvent cage, leading to B -pyridinium or B -ammonium boranephosphonate betaine derivatives. We found that the type of the solvent used (e.g., dichloromethane vs acetonitrile) significantly affected the course of the reaction, resulting in either formation of boron-modified derivatives or loss of the boron group with a subsequent oxidation of the phosphorus atom. In aprotic, electron-donating, polar solvents., e.g., acetonitrile (ACN) and tetrahydrofuran (THF), a λ 3 -boranephosphonate intermediate can also coordinate solvent molecules forming P-B-ACN or P-B-THF complexes that may influence the type of the products formed.

Mechanistic and stereochemical aspects of the reaction of boranephosphonate diesters with amines promoted by iodine were investigated. This is a complex, multistep reaction that ultimately produces the corresponding phosphoramidate diesters via a formal replacement of the borane group by an amine moiety. We found by a stereochemical correlation analysis that, contrary to a literature report, the whole transformation proceeded with total inversion of the configuration at the phosphorus center. Our study also showed that instead of the postulated nucleophilic substitution by iodide at the phosphorus center of the initially formed intermediate, the corresponding iodoboranephosphonate, the crucial step of the reaction involved intermediacy of H-phosphonate derivatives that reacted with iodine to afford ultimately phosphoramidate diesters. The reaction of the iodoboranephosphonate with the amine to produce an aminoboranephosphonate diester that rapidly dissociated into the corresponding H-phosphonate and the borane parts was apparently instrumental to the formation of an H-phosphonate diester intermediate.

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.

Formation of H-phosphonothioate diesters via condensation of H-phosphonate monoesters with a hydroxylic component in the presence of various coupling agents and possible side reactions that may accompany this process were studied using (31)P NMR spectroscopy. Optimal reaction conditions, which eliminate or significantly suppress the side reactions, have been designed and assessed in syntheses of dinucleoside H-phosphonothioate diesters.