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The use of O-arylphosphoroamidites in the synthesis of nucleosides phosphates of biological interest and their P–F analogues is described. This goal is achieved by extremely smooth reaction of O-arylphosphites with fluoride anion donors. Dinucleoside phosphorofluoridites RO(R′O)PF prepared by this method can be resolved into diastereoisomeric forms. Phosphorofluoroamidites –P(F)NR2 are efficient reagents in the synthesis of corresponding esters –P(F)OR′. These P(III)–F systems are employed in a new and effective synthesis of trifluoromethylphosphonite P(III)–CF3 by reaction with (trifluoromethyl)trimethylsilane (CF3SiMe3). This reaction, catalysed by the fluoride anion, can be part of a sequential procedure that combines formation of P(III)–F compounds with their transformation into the corresponding P(III)–CF3 system. To cite this article: J. Michalski et al., C. R. Chimie 7 (2004).

Oligonucleotides containing 3'- S -P(S) and 5'- S -P(S) fragments in the deoxy-series are available only by tedious multistep procedures. We have developed a novel and efficient methodology based on ring opening of anhydronucleosides by phosphorus dithioacids. This approach allows efficient synthesis of modified dinucleotides of the ribo-series.

A new convenient and general procedure is described for the preparation of mixed phosphites from readily available phosphorofluoroamidites by stepwise replacement of amino and fluoro-groups in the presence of trimethylchlorosilane (Me 3 SiCl). The reaction mechanism is briefly discussed.

The phosphine selenides, tris(dimethylamino)phosphine selenide, esters of selenophosphoric acid, and esters of selenophosphonic acid react with dihalogens and sulfuryl chloride to form halogenoselenophosphonium salts (P–SeX)+X−. The latter undergo deselenization via ligand exchange to form phosphonium salts (P–X)+X− and elemental selenium. The stability of these salts depends on the substituents at the phosphorus atom and the type of counter ion. It is likely that the phosphonium salts are in equilibrium with the corresponding phosphoranes, and this is demonstrated for esters containing an o-phenylene ligand. The structures of phosphonium salts, phosphoranes and other phosphorus compounds are supported by 31P NMR spectroscopy data and electrical conductivity. Additional evidence comes from addition reactions of halogenoselenophosphonium salts to cyclohexene.

2,4-Dinitrophenol (DNP) is a remarkably efficient activator in the reaction of P(III) amides with nucleosides to give P(III) esters in excellent yield. Typical examples of this novel procedure are presented herein. Mechanistic features of the activation were elucidated by model studies of the reaction of bis(2-cyanoethyl)diisopropylphosphoroamidite with benzyl alcohol. The importance of the initial protonation stage and formation of an intermediate P(III)-2,4-dinitrophenyl ester were clearly demonstrated by 31 P NMR spectroscopy and independent synthesis. New phosphitylating reagents containing the 2,4-dinitrophenoxy group do not require any activation.

The reaction of bis(phosphinoyl) diselenides R1R2P(O)Se–SeP(O)R1R21 with P(III) compounds has been investigated and its mechanistic features have been elucidated by variable temperature 31P NMR spectroscopy. These studies show that in most cases phosphonium intermediates 7, 13 and 10, 16 are involved. In the case when ligands on P(III) increase the stability of the five-coordinate structure, a phosphorane intermediate is observed. In the isomerization 7→10 and 13→16 the pathway of decomposition (deselenization, deoxygenation or dealkylation) to give stable end products is influenced by electronic and steric factors.

The reactions of azetidinium salts with phosphorus nucleophiles R2P(O)H have been investigated. Treatment of O-benzyl-N,N-diethyl-3-hydroxyazetidinium salt 2 with R2P(O)H in the presence of sodium hydride gave the corresponding γ-N,N-diethylamino-β-benzyloxypropylphosphonate 6a or phosphine oxide 6b. After debenzylation γ-N,N-diethylamino-β-hydroxypropylphosphonate 3a and phosphine oxide 3b were obtained. The compound 6a was converted into its sulfonate ester 8 which underwent elimination to yield 4. The structure 4 has been employed in Michael addition of R2P(O)H to form compounds 5 containing two phosphorus centers. Further compounds of type 3 have been transformed into compounds 5 by reaction with R2P(O)H in the presence of 1.1 equivalents of NaH in boiling toluene. Finally, azetidinium salts 1 have been converted into compounds 5a by reaction with two equivalents of R2P(O)H in the presence of 2.1 equivalents of NaH. Molecular mechanics with implementation of the Allinger MM2 force field and semiempirical AM1 and PM3 methods were used to investigate structures 5d and 5f.

A stereospecific synthesis of P-chiral sulfenyl chlorides 6a,b has been developed from P-chiral sulfenylamide 9a,b,c by a novel procedure employing 2Me 3 SiCl + 2EtOH as the reagent of choice. The sulfenylamides 9a,b,c were prepared either by stereospecific reaction of the P-chiral hydrogen phosphinothioate 8a with aminosulfenyl halides or separation of a mixture of diastereomeric 9a,b,c by crystallisation. P-Chiral chlorides 6a,b were allowed to react with secondary amines such as morpholine or dicyclohexyl amine. All these displacement reactions proceed with almost complete stereochemical integrity at the phosphorus atom. These abservations support a synchronous mechanism of bond breaking and bond formation during nucleophilic displacement at the dicoordinate sulfur atom. The same can be said about the reaction of sulfenamides 9a,b,c with hydrogen chloride.

The reaction of perbenzylated (±)-myo-inositol 1,2-bis- and 1,2,6-tris-phosphites with benzyl bromoacetate, followed by catalytic ( Pd C ) hydrogenolysis affords (±)-myo-inositol 1,2-bis- and 1,2,6-tris(carboxymethylphosphonate). The same procedure is used for the synthesis methyl α-D-mannopyranoside 2,3,4-tris(carboxymethylphosphonate).

Novel and efficient synthesis of polyfunctional γ- and δ-aminophosphonic acids derivatives via ring opening of 3-alkoxyazetidinium salts with phosphorus containing nucleophiles is described.

An efficient procedure is described that leads to pure (SP)-O-l-menthylphenylthiophosphinate. The absolute configuration of this diastereomer was assigned by chemical correlation and confirmed by X-ray crystallography. The reaction of the isomer with phenyl azide, leading to amidate, is a new variant of the stereoselective Staudinger reaction. Addition of elemental selenium to the (SP)-thiophosphinate led to diastereomeric O-l-menthylphenylselenophosphonothioic acid, which was finally oxidized to the diastereomeric (RP1,RP2)-bis-[O-l-menthylphenylphosphonothionyl] diselenide. The diselenide structure was unambiguously confirmed by 31P NMR spectroscopy.

P-Chiral (Rp)(dicyclohexylaminosulfanyl)[(–)-p-menthan-3-yloxy]phenylthioxophosphorane 1 was synthesized by condensation of (Sp)(–)-p-menthlan-3-yl phenylthiophosphinate 2 and (H11C6)2NSBr. The reaction proceeds with retention of configuration at the chiral phosphorus centre. Compound 1 crystallized from chloroform–acetone or chloroform as two polymorphs in proportions depending on the solvent. X-Ray crystallography revealed that in the asymmetric part of the unit cell polymorph 1 contains two independent molecules with anti and syn geometry of the SP–S–N fragment and polymorph 1′ contains only one independent molecule with anti geometry. Preliminary structural results were obtained by analysis of 31P cross-polarization magic angle spinning NMR spectra. The SP–S bond angles, P–S and PS bond lengths were established from the anisotropy Δδ and principal components of the chemical shift tensor, δ22 and δ33, respectively. Comparison of geometrical parameters obtained from solid-state NMR spectroscopy with those from X-ray diffraction analysis of single crystals confirms the accuracy of this approach. For the anti SP–S–N conformation the SP–S bond angle is smaller than the tetrahedral value, and the P–S bond length is 2.09 A. The syn geometry is associated with a larger SP–S valence angle and longer P–S bond. The trend towards planarity is explained in terms of a π contribution to the P–S single bond.

Reaction of phosphorus acids bromides and iodides with silver salts of sulfonic acids leads to the formation of mixed phosphorus and sulfonic acids anhydrides 3 in excellent yield. This method allowed the first synthesis of mixed anhydrides containing a P-chiral centre; they were subsequently separated into pure diastereoisomers.

Stereoselective synthesis of the P-chiral thioxaphosphoranesulfenyl (dicyclohexyl)amide (l-menthyl-O)PhP(S)SN(C6H11)2 and its conversion into the P-chiral thioxaphosphoranesulfenyl chloride (l-menthyl-O)PhP(S)SCl is described. First synthesis of P-chiral thioxaphosphoranesulfenyl bromides (l-menthyl-O)PhP(S)SBr via the bromolysis of the bis-thiophosphoryl disulfide [(l-menthyl-O)PhP(S)S-)]2 is presented. Transformations of P-chiral thioxaphosphoranesulfenyl chlorides and bromides into the corresponding sulfenamides proceed with the preservation of stereochemical integrity at the chiral P-center.

The reaction of readily available dialkyltrimethylsilyl phosphites (RO)2POSiMe3 5 with sulfur dichloride leads to tetra-alkyl sym-monothio-pyrophosphates (RO)2P(O)SP(O)(OR)2 1 in high yield. The method is suitable for the synthesis of tetra t-butyl thiopyrophosphate 1d.

The reactions of bis(phosphinoyl) disulfides RR1P(O)S–S–P(O)RR11 with PIII compounds have been investigated and various mechanistic features have been elucidated by variable-temperature 31P NMR spectroscopy. These studies show that in most cases phosphonium intermediates [[graphic omitted]P(O)–S–[graphic omitted]–O–P(S)[graphic omitted]]5 and [[graphic omitted]P(S)–O–[graphic omitted] –O–P(S)[graphic omitted]]6 are involved. In cases where ligands on PIII increase the stability of the five-coordinate structures phosphorane intermediates are observed. In the isomerization 5→6, the mode of decomposition (desulfurization, deoxygenation or dealkylation) to give stable end products is influenced by electronic and steric factors. The presence of the Lewis acid BF3 influences considerably the stability of the transient species 5 and 6 and the chemoselectivity of the reaction.

Tetra- and tri-coordinate P–N-imidazole derivatives and their structural analogues react smoothly with acyl fluorides to give the corresponding P–F compounds in almost quantitative yield. This method has been successfully applied to produce 2-deoxynucleosidyl phosphorofluoridates and phosphorodifluoridates.

A new synthetic approach to modified oligonucleotides based on N,N′-diisopropyl-di-(4-nitrophenyl)phosphoroamidite 1 is described. The procedure involves displacement of either 4-nitrophenoxy or diisopropylamino ligands. The former proceeds very fast in the presence of DBU, the latter requires activation by tetrazole. This method allows rapid and almost quantitative construction of modified nucleotides derived from thio- and selenophosphorus acids.

Internucleoside coupling by the title reagent, illustrated by synthesis of dinucleoside and trinucleoside thiophosphates and selenophosphates is accomplished by a new strategy involving the displacement of 4-nitrophenoxy group. Sodium 4-nitrophenolate formed in situ facilitates the oxidation of the intermediate pIII structures and acts as a demethylating reagent.

Synthetic oligonucleotides bearing modifications in the backbone have potentials as tools in studying and controlling biological processes.

Fluoroderivatives of phosphorus are important in the chemistry and biochemistry of both elements.1. Recently, our attention has been Focused on the synthesis of non-ionic oligodeoxynucleoside-phosphoro fluoridates and their thio− and selenoanalogues. Existing methods were, in our opinion, not suited for the synthesis of oligonucleoside− phosphorofluorides. So we devised new ones.

The structure and dynamics of selected bis(organothiophosphoryl) disulfides have been studied by single-crystal X-ray diffraction and high-resolution solid-state NMR spectroscopy. The crystal and molecular structures of bis[tert-butyl(phenyl)thiophosphoryl] disulfide 1, bis-(diphenoxythiophosphoryl) disulfide 2 and bis[tert-butyl(methoxy)thiophosphoryl] disulfide 3 were determined, giving space groups of C2/c, P212121 and P for 1, 2 and 3, respectively. Both phosphorus centres of the disulfide 1 have the same absolute configuration, as have those of the disulfide 3, although their environments were significantly different. It has been unambiguously proved that the S–S disulfide bond length varies as a function of the PSSP torsional angle. Moreover the influence the S–S–PS conformation has on the P–S bond length is discussed. Carbon-13 NMR dipolar-dephasing experiments, using powdered samples, indicated that both the tert-butyl and methoxy groups attached to the phosphorus atom were in a fast regime exchange.

Reaction between oxophosphoranesulfenyl chloride 1(R = R′= EtO) and o-phenylene neopentyl phosphite 4 takes predominantly the deoxygenation course, yielding the phosphorochloridothioate 7 and the phosphate 8. Formation of minor products 5 and 6 corresponding to the desulfurization pathway, and low-temperature 31P NMR observations, are rationalized by proposing phosphoranephosphonium equilibria which are shifted towards phosphorane structures 9, 13, 11. These results supplement our earlier studies on desulfurization and deoxygenation of compound 1 with tricoordinate phosphorus compounds and add new evidence for phosphonium–phosphorane equilibria.

Fluoroderivatives of phosphorus are important in the chemistry and biochemistry of both elements.1. Recently, our attention has been Focused on the synthesis of non-ionic oligodeoxynucleoside-phosphoro fluoridates and their thio− and selenoanalogues. Existing methods were, in our opinion, not suited for the synthesis of oligonucleoside− phosphorofluorides. So we devised new ones.

Trifluoroacetic anhydride reacts with organophosphorus compounds containing thiophosphoryl and selenophosphoryl groups converting them in high yield to the corresponding oxygenated systems.

Trimethylchlorosilane (TMSCl) is a remarkably efficient activator in the reaction of phosphorus(III) amides with nucleosides to give phosphorus(III) esters in excellent yield.

Stereoselective synthesis of phosphocarnitine has been achieved for the first time starting from R(−)-epichlorohydrin.

The reactions of azetidinium salts with phosphorus nucleophiles R2P(O)H have been investigated. Treatment of O-benzyl-N,N-diethyl-3-hydroxyazetidinium salt 2 with R2P(O)H in the presence of sodium hydride gave the corresponding γ-N,N-diethylamino-β-benzyloxypropylphosphonate 6a or phosphine oxide 6b. After debenzylation γ-N,N-diethylamino-β-hydroxypropylphosphonate 3a and phosphine oxide 3b were obtained. The compound 6a was converted into its sulfonate ester 8 which underwent elimination to yield 4. The structure 4 has been employed in Michael addition of R2P(O)H to form compounds 5 containing two phosphorus centers. Further compounds of type 3 have been transformed into compounds 5 by reaction with R2P(O)H in the presence of 1.1 equivalents of NaH in boiling toluene. Finally, azetidinium salts 1 have been converted into compounds 5a by reaction with two equivalents of R2P(O)H in the presence of 2.1 equivalents of NaH. Molecular mechanics with implementation of the Allinger MM2 force field and semiempirical AM1 and PM3 methods were used to investigate structures 5d and 5f.

We describe the convenient synthesis of thymidine cyclic 3', 5'-phosphorofluoridate 6, which is superior to that previously reported. Our procedure is based on a sequence of reactions utilizing 3 as the key substrate. Similar sequence of reaction leads to the sulfur analogues of 6 the thymidine cyclic 3',5'-phosphorofluoridothioate 7.

The reaction of oxophosphoranesulfenyl chlorides RR'P(O)SCl 2 with P III compounds has been investigated. Its mechanistic features have been elucidated by variable-temperature 31 P NMR spectroscopy and stereochemical changes at P IV and P III phosphorus centers. These studies show that in all cases phosphonium intermediates containing the sulfur bridge>P(O)-S-P

Trimethylsilyl esters of general formula RR′POSiMe3 react in a quantitative and fully chemoselective way with sulfuryl chloride fluoride, ClSO2F, under extremely mild conditions to give phosphorofluoridates RO(R′O)P(O)F of high purity. This work provides easy access to all type of fluoridates from non-toxic starting materials. The synthetic usefulness of this method is illustrated by the synthesis of 3′- and 5′-mononucleoside phosphorofluoridates 10 and 3′,5′-dinucleoside phosphorofluoridates 11 from the corresponding nucleoside trimethylsilyl phosphites.

Activation of phosphoramidites as phosphitylating reagents in the synthesis of biophosphates and their structural analogues is of great importance. Tetrazole a customary activator can be conveniently replaced by trimethylchlorosilane (TMCS) or 2,4-dinitrophenol. Advantages of use of these reagents in the synthesis of biophosphates and their mechanism of action are discussed. Phosphites containing 4-nitrophenoxy leaving group are activated by DBU which role is revealed. Readily accessible P(III)-F structures, can be "activated" by their facile transformation into the corresponding bromides using trimethylbromosilane (TMBS). Application of phosphoramidites in synthesis of phosphates of biological interest and their activation by azolides and acids salts, including and stereochemical aspects was described in 'Topics in Current Chemistry.

Unprecedented CP systems: Me3SiX (X=Br, I) catalyses rearrangements of PIII esters R′R′′POR into the corresponding phosphoryl systems, providing a simple, mild and efficient route to a variety of structures containing PC bonds. The mechanism has been found to be fundamentally different from that of the Arbuzov–Michaelis reaction and includes three definite steps a, b and c (see scheme). Halotrimethylsilanes Me3SiX (X=Br, I) catalyse rearrangements of tricoordinate phosphorus esters R′R′′POR into the corresponding phosphoryl systems R′R′′P(O)R. This provides a simple and efficient route to a variety of structures containing phosphoruscarbon bonds, under mild conditions and with good yields. The reaction mechanism was investigated in detail by 31P NMR spectroscopy and independent synthesis of the reaction intermediates. It has been demonstrated that the primary products of this catalytic reaction are halogeno PIII structures R′R′′PX and silyl ethers ROSiMe3 and that they subsequently react to give the corresponding phosphorus silyl esters—Me3SiOPR′R′′—and alkyl halides RX. At higher temperatures these intermediates then react to form R′R′′P(O)R compounds. This paper also features the surprising observation that when esters Ph2POR and halotrimethylsilanes Me3SiX (X=Br, I) are used in 2:1 ratio, phosphonium salts Ph2R2P+X− and trimethylsilyl diphenylphosphinate—Ph2P(O)OSiMe3 —are formed as the major products. Experimental evidence indicates that the mechanisms of both reactions are fundamentally different from that of the Michaelis–Arbuzov reaction. Me3SiCl is not reactive and this paper explains why.

The mechanistic and synthetic aspects of the addition reaction of thioxophosphorane sulfenyl bromide with ethyl vinyl ether were studied in detail by NMR techniques. It has been found that the regiospecific, primary product of the reaction, 1-bromo-1-ethoxy-2S(dialkoxythiophosphoryl)ethane I, is unstable and undergoes slow decomposition to give four compounds. The formation of thiophosphoryl derivatives, vinyl ethers II and III, aldehyde IV, and the symmetrical hemiacetal anhydride V, has been considered in terms of a carbocation intermediate. By choice of the appropriate reaction conditions, the aldehyde IV can be obtained in very high yield.

First example of the PIII coupling reagent containing 4-nitrophenoxy group is described. Its usefulness is demonstrated by synthesis of dinucleoside methylphosphonate and methylthiophosphonate.

The interaction of 1,2-aIkadienephosphonic derivatives with phosphorus containing pseudohalogenes affords 2,5-dihydro-1,2-oxaphospholene derivatives. The structure of the new compounds is determined by NMR and IR spectroscopy.

The reaction of diastereoizomeric 3′-[5′-O-(monomethoxytrityl)thymidyl]-5′-(3′-O-monomethoxytrityl)thymidine O-methyl phosphoro-thioate and 3′-[5′-O-(monomethoxytrity1) thymidy1]-5′-(3′-O-monomethoxytrityll-N6 -benzoyladenosine O-methyl phosphorothioate with sulfuryl-chloride fluoride leads to the corresponding diastereoisomeric phosphorofluoridates in highly stereoselective manner.

Phosphoranesulphenyl halides of the general formula RR'P(Y)SX and their selenium analogues RR'P(Y)SeX (X=Cl,Br; Y=O,S) have been shown to be useful intermediates for access to many new classes of compounds con-taining phosphorus, sulphur, or selenium centers.'

Trifluoroacetic anhydride reacts with organophosphorus compounds containing thiophosphoryl and selenophosphoryl groups converting them in high yield to the corresponding oxygenated systems.

This chapter is concerned with preparation and applications of tricoordinate phosphorus compounds in synthesis of biophosphates and their structural analogues and illustrates the recent trends with a series of selected examples.

A new way of forming P-C bonds: Catalytic amounts of F- ions facilitate the reaction of PIII -F compounds with CF3 SiMe3 to give PIII -CF3 compounds. These compounds can also be obtained in a one-pot procedure from PIII -OAr precursors (also shown).