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We have designed a new type of AZT and ddU phosphoramidate diesters containing various combinations of 2-, 3-, 4-aminopyridine and 2-, 3-, 4-hydroxypyridine moieties attached to the phosphorus center, as potential anti-HIV pronucleotides. Depending on the pK a values of the aminopyridines and the hydroxypyridines used, alternative synthetic strategies based on H-phosphonate chemistry were developed for their preparation. Synthetic aspects of these transformations and the biological activity of the synthesized compounds are discussed., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

This review covers recent progress in the preparation of H-phosphonate mono- and diesters, basic studies on mechanistic and stereochemical aspects of this class of phosphorus compounds, and their fundamental chemistry in terms of transformation of P-H bonds into P-heteroatom bonds. Selected recent applications of H-phosphonate derivatives in basic organic phosphorus chemistry and in the synthesis of biologically important phosphorus compounds are also discussed.

Efficiency and stereoselectivity of condensations of ribonucleoside 3'-H-phosphonates with ethanol promoted by pivaloyl chloride were investigated as a function of tertiary amines used. Side reactions leading to an increased demand for the condensing agent were identified as derived from an attack of the pivalate anion at carbonyl centers of reactive pivaloyl derivatives. The conditions that secured quantitative yields of H-phosphonate diester condensations were assessed. Several tertiary amines promoted condensations with stereoselectivity higher than that observed for pyridine derivatives. A correlation between diastereoselectivity of the product formation and Brønsted and H-bonding basicities of the amine used was found.

A general and efficient method for the microwave-assisted formation of the C-P bond was developed. Using a prevalent palladium catalyst, Pd(PPh3)4, a quantitative cross-coupling of various H-phosphonate diesters with aryl and vinyl halides was achieved in less than 10 min. The reactions occurred with retention of configuration at the phosphorus center and in the vinyl moiety. Using this protocol, several C-phosphonates, including those bearing nucleoside and cholesteryl moieties, were prepared in high yields.

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.

It was found that nucleoside H-phosphonothioate, H-phosphonodithioate, and H-phosphonoselenoate monoesters in the presence of iodine underwent rapid oxidative esterification with various hydroxylic components to produce in "one pot" reactions the corresponding nucleoside phosphorothioate, nucleoside phosphorodithioate and nucleoside phosphoroselenoate diesters in good yields. The transformation represents a novel alternative method for the synthesis of internucleotide phosphate bridge, bearing sulfur or selenium atoms. Mechanistic studies have revealed metaphosphate analogues as the probable intermediates, involved in the reactions.

It was found that in stereoselective condensations of ribonucleoside 3'-H-phosphonates with alcohols, the major diastereomer of the produced H-phosphonate diesters is formed from the minor diastereomer of the intermediate phosphonic-pivalic anhydride.

In this paper a short account of our recent basic studies aiming toward development of new synthetic methods for the preparation of nucleotide analogues using H-phosphonate chemistry is presented.

In this chapter, a concise account of the synthesis of oligonucleotides using the H-phosphonate methodology is given. It includes various methods for the preparation of the starting material, nucleoside 3'-H-phosphonate monoesters, their conversion into dinucleoside H-phosphonate diesters, oxidative transformations of dinucleoside H-phosphonates into the corresponding phosphate and phosphorothioate derivatives, and protocols for the synthesis of oligonucleotides and their phosphorothio analogs.

An efficient entry to nucleoside 3'-H-phosphonoselenoate monoesters via phosphinate intermediates was developed. It involves a reaction of suitably protected nucleosides with triethylammonium phosphinate in the presence of pivaloyl chloride, followed by selenization of the intermediate nucleoside phosphinates with triphenylphosphine selenide, to produce the corresponding nucleoside H-phosphonoselenoates in 86-92% yields.

Oligonucleotides can be synthesized by condensing a protected nucleoside H-phosphonate monoester with a second nucleoside in the presence of a coupling agent to produce a dinucleoside H-phosphonate diester. This can then be converted to a dinucleoside phosphate or to a backbone-modified analog such as a phosphorothioate or phosphoramidite. This unit discusses four alternative methods for synthesizing nucleoside H-phosphonate monoesters. The methods are efficient and experimentally simple, and use readily available reagents. The unit describes the activation of the monoesters, as well as competing acylation and other potential side reactions.

An efficient and stereospecific synthesis of dinucleoside 4'-(2,2':6',2''-terpyridyl)phosphonate 2 and 5-(2,2'-bipyridyl)phosphonate 3 via a palladium(0) cross coupling strategy has been developed.

This paper expands the available methods for preparation of H-phosphonoselenoate using a new reagent, 9-fluorenemethyl H-phosphonoselenoate.

Chemoselectivity and stereospecificity of iodine mediated oxidative couplings using separate diastereomers of dinucleoside H-phosphonate and H-phosphonothioate with various N- and O-binucleophiles were investigated.

In this paper a short account of our recent research concerning the development of new synthetic methods and reagents for the preparation of nucleotides and their analogues, is given.

The biological importance and practical significance of phosphate esters and their analogues have been the major driving forces for research in various areas of synthetic organic phosphorus chemistry. In this Account, the authors' studies on the development of a comprehensive H-phosphonate methodology and the underlying chemistry for the preparation of biologically important phosphate esters and their analogues are briefly discussed.

Configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of diazabicyclo[5.4.0]undec-7-ene (DBU) were investigated using 31P NMR spectroscopy. It was found that under the reaction conditions and irrespective of the type of protecting groups present in the nucleoside moieties, the H-phosphonate diesters investigated did not undergo any detectable epimerisation at the phosphorus centre, and their sulfurisation with elemental sulfur in the presence of DBU, proceeded stereospecifically. Thus, we could not confirm reports from another laboratory on a stereoselective course of sulfurisation of H-phosphonate diesters and the corresponding acylphosphonates in the presence of DBU.

Most methods for preparing H-phosphonate monoesters suffer from variable yields and are often incompatible with common protecting groups used in oligonucleotide synthesis. This unit describes four procedures that consistently give high yields of the desired products. Taken together, they provide an arsenal of phosphonylation procedures that it compatible with most common protecting groups.

Chemical synthesis of nucleoside-phospholipid conjugates based on hydrogenphosphonate chemistry has been achieved via coupling of 1,2-dipalmitoylglycero-3-H-phosphonate with suitable protected nucleosides or via coupling of nucleoside H-phosphonates with 1,2-dipalmitoylglycerol. It was also found that 1,2-dipalmitoylglycero-3-H-phosphonate, which is a stable compound, can serve as a convenient intermediate in the synthesis of various phospholipids.