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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.

AbstractNew analogs of dUMP, dTMP and 5-fluorodUMP, including the corresponding 5thiophosphates (dUMPS, dTMPS and FdUMPS), 5dithiophosphates (dUMPS2, dTMPS2 and FdUMPS2), 5Hphospho nates (dUMPH, dTMPH and FdUMPH) and 5S thiosulfates (dUSSO3, dTSSO3 and FdUSSO3), have been synthesized and their interactions studied with highly purified mammalian thymidylate synthase. dUMPS and dUMPS2 proved to be good substrates, and dTMPS and dTMPS2 classic competitive inhibitors, only slightly weaker than dTMP. Their 5-fluoro congeners behaved as potent, slowbinding inhibitors. By contrast, the corresponding 5Hphosphonates and 5Sthiosulfates displayed weak activities, only FdUMPH and FdUSSO3 exhibiting significant interactions with the enzyme, as weak competitive slowbinding inhibitors versus dUMP. The pHdependence of enzyme timeindependent inhibition by FdUMP and FdUMPS was found to correlate with the difference in pKa values of the phosphate and thiophosphate groups, the profile of FdUMPS being shifted (~1 pH unit) toward lower pH values, so that binding of dUMP and its analogs is limited by the phosphate secondary hydroxyl ionization. Hence, together with the effects of 5Hphosphonate and 5Sthiosulfate substituents, the much weaker interactions of the nucleotide analogs (35 orders of magnitude lower than for the parent 5phosphates) with the enzyme is further evidence that the enzymes active center prefers the dianionic phosphate group for optimum binding.

The final product of the reaction of H-phosphonate monoesters with diphenylchlorophosphate was found to be the corresponding dichlorophosphite. Stericalty hindered aromatic acyl chlorides react with H-phosphonate diesters affording C-phosphonate derivatives.

A chemically synthesised duplex DNA fragment containing the sequence of the lac operator was cloned in E. coli using the vehicle pMB9. Clones containing lac-pMB9 hybrid DNA produced β-galactosidase constitutively and the hybrid DNA bound the lac repressor specifically.

Aryl nucleoside H-phosphonates 3 and aryl nucleoside P-acylphosphonates 4, generated in situ from the appropriate H-phosphonate 1 and acylphosphonate monoesters 2, respectively, reacted rapidly in the presence of tertiary amines to produce in high yields the extended, pyrophosphate analogues, diaryl dinucleoside phosphonate−phosphate derivatives 6. These, depending on a substituent on the α-carbon of the phosphonate moiety, either underwent transformation into the dinucleoside phosphonate−phosphate 7 or afforded nucleoside H-phosphonates 8 and aryl nucleoside phosphate 9.

Various arylsulfonyltetrazoles have been investigated to build the phosphotriester bond between appropriately protected oligonucleotides. These reagents have been found to be highly effective with respect to the time of reaction and yields.

AbstractThe synthesis of some symmetrical phosphoramidate dimers of AZT is presented. The synthetic scheme includes the formation of the symmetrical H-phosphonate diester of AZT, followed by its conversion to several dinucleoside phosphoramidate analogues. The compounds were evaluated for their anti-retroviral activity.

[image omitted]Condensation of 5'-O-monomethoxytrity1-2'-O-t-butyldimethylsilyl- uridine 3'-H-phosphonate (triethylammonium salt) (1) with 2',3'-0- dibenzoyluridine (2) using pivaloyl chloride (PV-C1)1, 2-chloro-5,5- dimethyl-l,3,2-dioxaphosphorinane 2-oxide (NPCP)2 and bis(2-oxo-3- oxazolidiny1)phosphinic chloride (OXPI2 as condensing agents, has been investigated. Pyridine or quinoline3 was used as a base and nucleophilic catalyst in the following solvent systems: neat pyridine or quinoline, pyridine (or quinoline)/acetonitrile (4:1, v/v,), pyridine (or quinoline)/acetonitrile (1 :1, v/v,), and pyridine (or quinoline)/acetonitrile (1:4, v/v,). Stoicheiometric amounts of 1 and 2 (concentration 25 pM) and 3 equiv. of the appropriate condensing reagent were used in all reactions.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The mechanism of the reaction between the α‐D‐galactopyranose (Ia) and the title reagent system to give the product (Ib) is studied in three solvent systems: toluene‐acetonitrile (2:1), acetonitrile, and pyridine.

The dipalmitoyl glycerol (I) is converted to the phosphonate (III) which reacts with hydroxylic components such as the N‐protected ethanolamine (IV) in the presence of a condensing agent to form the diester (V).

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The modified triester approach has been further improved and refined to the synthesis of defined sequences of deoxyribooligonucleotides. Improvements include arylsulfonyltetrazoles as faster and milder condensing agents, benzenesulfonic acid to avoid depurination during deblocking of trityl protecting groups and improved chromatographic procedures for purification of triester intermediates and purification of the final product containing 3′-5′ phosphodiester linkages. The efficiency of these new modifications in terms of yields and time has been illustrated by the synthesis of various defined sequences related to the lactose-operator region of E. coli, its analogues and two restriction enzyme recognition regions.

Among some methods for oxidation of phosphonates such as (I) the use of I2 proves to be the most efficient procedure.

The title reaction proceeds via the trimetaphosphite (V), the formation of which is facilitated by the presence of a base (pyridine).

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The sulfonation of nucleosidic component, a side reaction during phosphotriester bond formation, as a function of the reactivity of the condensing agents and the kind of substituents in the starting phosphodiester is discussed. It was found that in the coupling reaction of nucleoside alkyl phosphodiesiers, the degree of sulfonation of the nucleosidic component was very high; while under the same conditions when the aryl group was present in the corresponding phosphodiester, this side reaction practically did not occur.

The synthesis of oligodesoxy‐ribonucleotides such as (III) by the hydrogenphosphonate approach is described.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

In this work, the first example of chemical synthesis of oligoribonucleotide containing the hypermodified nucleoside N6-/N-threonylcarbonyl/-adenosine/t6A/ is presented. Synthesis of the heptamer C-C-C-A-U-t6A-A IX, the sequence of which is related to the anticodon loop of the initiator tRNA from yellow lupine, was achieved by: /i/ phosphotriester block synthesis of suitably protected heptamer VI containing an adenosine unit with a free exo-NH2 group, /ii/ highly effective “one-flask” procedure for the transformation of the free exo-NH2 group of adenosine unit of heptamer VI into a N,N′-disubstituted urea system of t6A of heptamer VII /hypermodification/, and /iii/ final deprotection of VIII /32% total yield/ with the use of a new approach for simultaneous hydrogenolysis /Pd0-hydrogen-pyridine/ of the p-nitrobenzyl group and 2,2,2-trichloroethyl groups from carboxyl function of t6A and internucleotide phosphates respectively.