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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.

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.

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 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.

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.'

As part of our studies on the synthesis of mono- and bis-phosphonic acids, phosphine oxides and phosphines containing amino and hydroxy groups attached to tricarbon or tetracarbon chains [I], we now report our efforts to find a rational synthesis of compounds 2,3 and 4: Reagents: (a):R5R6PCH2Y, BuLi; (b): R3R4P(O)H, NaH; (c): 1. Pd/C, H2, 2 TsCl, Py; (d): 1 BuOK, BuOH, 2 R7 R2 P(Z)H, NaH.

Reaction of trifluoroacetic anhydride with chloroanhydrides of phosphorus acids R2P(O)CI results in formation of mixed anhydrides R2P(O) OCOCF3 and trifluoroacetic acid halides CF3COX (X=Cl, Br, I) in quantitative yield.

The azolides of general formula 1 are readily available 1 and can be transformed in quantitative way by acyl fluorides or oxalyl fluoride into the corresponding P- fluorides 2. This strategy was extended towards synthesis of difluorides R-P(X)F 2 and trifluorides P(X)F 3 . The method was also successfully applied in chemistry of P-F modified nucleotides. e.g.

Continuing our studies on new reaction of trimethylsilylphosphites 1 we now report the conversion of compounds 1 to the corresponding phosphorazolides or phosphoranilidates by the reaction of readily available trimethylsilylphosphites 1 and 1,l'-oxalyldiazolides or anilidates.

Organic monopyrophosphates, structural analogues of biologically important diphosphates, undergo spontaneous thiolo-thiono isomerization (1). On the basis of the detailed kinetic mechanistic studies of the isomerization of bis(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane) 1 in 1-methylnaphtalene (MN), beiizoiiitryle or propylerie carbonate solutions the dissociative mechanism has been proposed (2): To support this mechanism we hove studied the kinetics of isomerization of 1 labelled with 35S in pyridine (Py) solutions. As To support this mechanism we hove studied the kinetics of isomerization of 1 labelled with 35S in pyridine (Py) solutions. As expected the reaction is very fast. The first-order reaction rate constant in Py at 25°C is about 107 times greater then the value obtained by extrapolation of the kinetic data for the reaction in MN. The reaction rate constant in Py solutions is almost not sensitive to triethylanunonium salt of the acid AH. This demonstrates that the dissociative step (k1...

Interaction between some 1,2-alkadienephosphonic derivatives and dimethyl(diisopropyl)phosphonic sulfenyl chlorides in weak polar media was investigated. We established that in all cases the oxaphospholic cyclization of 1,2-alkadienephosphonic system took place, and 4-thiodi-alkoxyphosphonyl-2,5-dihydro-l,2-oxaphospholic derivatives were obtained.

The reaction of acyclic oxophosphoranesulphenyl chlorides, with phosphorus trichloride has been found to give thiophosphoryl chlorides, and phosphoryl oxychloride—the products of the exclusive deoxygenation of sulphenyl chloride. Optically active phosphonochloridothionates and phosphorochloridothionates in a high state of optical purity have been obtained with inversion of configuration from optically active sulphenyl chlorides and phosphorus trichloride. It has been shown, however, that cyclic oxophosphoranesulphenyl chlorides undergo simultaneous desulphurisation and deoxygenation when treated with phosphorus trichloride. Using cis- and trans-isomers of 2-chlorothio-4-methyl-1,3,2-dioxaphosphorinan-2-one it has been demonstrated that deoxygenation is accompanied by inversion, whereas desulphurisation occurs with retention at phosphorus. The mechanism of the title reaction is discussed.

Earlier works from this and other laboratories on phosphoric and phosphinic sulfonic anhydrides have been reinvestigated. It was found that no single reaction described in the past provides a general method for the production of mixed anhydrides RR′P(O)SO2R″ (3) in high yields of isolated products. The following three efficient synthetic procedures leading to pure anhydrides 3 are described: a) Trifluoromethanesulfonic acid promoted reaction of phosphinic acid 9 with sulfonic triazolides 10. b) Reaction of phosphinic and phosphoric imidazolides 13 with sulfonic acid 6. c) Reaction of 13 with sulfonic anhydride 15. All methods result in high yields. Some chemical properties of the anhydrides 3 are described. Phosphorsaure- und Phosphinsaure-sulfonsaure-anhydride – Neuuntersuchung und Korrekturen. Neue Synthese-Methoden Fruhere Ergebnisse aus unseren und anderen Laboratorien an Phosphorsaure- und Phosphinsaure-sulfonsaure-anhydriden wurden uberpruft. Es wurde jetzt gefunden, das sich keine einzige fruher beschriebene Reaktion als allgemeine Methode zur Darstellung gemischter Anhydride RR′P(O)SO2R″ mit hohen Ausbeuten an isolierten Produkten eignet. Die folgenden drei Verfahren zur Synthese von reinen Anhydriden 3 werden beschrieben: a) Die Trifluormethansulfonsaure-katalysierte Reaktion von Phosphinsaure 9 mit Sulfonsaure-triazoliden 10. b) Reaktion von Phosphinsaure- und Phosphorsaure-imidazoliden 13 mit der Sulfonsaure 6. c) Umsetzung von 13 mit Sulfonsaureanhydrid 15. Alle Methoden ergeben hohe Ausbeuten. Einige chemische Eigenschaften der Anhydride 3 werden beschrieben.

New applications of methods leading to anhydrides RR′P(O)OSO2R″ (1) are described: a) Reaction of acids RR′P(O)OH (2) with sulfonic imidazolides. b) Reaction of phosphorus imidazolides 4 with sulfonic acids and sulfonic anhydrides. New Methods of synthesis of anhydrides 1 have been developed. c) Reaction of phosphorus acid silyl esters RR′P(O)OSiMe3 (9) with methanesulfonic and trifluoromethanesulfonic anhydrides. d) Reaction of bis(trimethylsilyl) tert-butyl-phosphonate (10) with methanesulfonic acid leading to t BuP(O)(OSO2Me)2 (11). e) Reaction of stannyl phosphate (EtO)2P(O)OSnMe3 (15) with methanesulfonic anhydride. f) Reaction of phosphorus acid silyl esters 9 with trimethylsilyl trifluoromethanesulfonate. All methods result in high yields and can be adapted to a variety of anhydrides 1 derived from phosphoric, phosphonic, and phosphinic acids on the one hand and methanesulfonic, trifluoromethanesulfonic acids and sulfuric monoimidazolide on the other. Phosphonium intermediates have been demonstrated by low temperature FT 31P NMR spectroscopy for reaction b) and c). The anhydrides 1 are readily converted into imidazolides 4 by the reaction with N-(trimethylsilyl)imidazole which proceeds via two distinct phosphonium intermediates. With neutral and weakly basic nucleophiles, the anhydrides 1 behave as phosphorylating agents. Anhydride aus Sauren des Phosphors und des Schwefels, 2. Gemischte Anhydride von Phosphor-, Phosphon- und Phosphinsauren mit Sulfonsauren und Schwefelsaure-monoimidazolid. Neue Synthesen, neue Verbindungen und ihre Eigenschaften als Phosphorylierungsmittel Es werden neue Anwendungen der Methoden, die zu Anhydriden der Struktur RR′P(O)OSO2R″ (1) fuhren, beschrieben: a) Die Reaktion von Sauren RR′P(O)OH (2) mit Sulfonsaure-imidazoliden. b) Die Reaktion von Imidazoliden 4 von Sauren des Phosphors mit Sulfonsauren und Sulfonsaure-anhydriden. Neue Methoden zur Synthese von Anhydriden der Struktur 1 wurden entwickelt. c) Die Reaktion von Trimethylsilylestern von Sauren des Phosphors RR′P(O)OSiMe3 (9) mit Methansulfonsaure- und Trifluormethansulfonsaure-anhydriden. d) Die Reaktion von tert-Butylphosphonsaure-bis(Trimethylsilylester) (10) mit Methansulfonsaure zu tBuP(O)(OSO2Me)2 (11). e) Die Reaktion des Stannylphosphats (EtO)2P(O)OSnMe3 (15) mit Methansulfonsaure-anhydrid. f) Die Reaktion von Trimethylsilylestern 9 von Sauren des Phosphors mit Trifluormethansulfonsaure-trimethylsilylester. Alle Methoden ergeben hohe Ausbeuten und konnen an die Vielzahl der Anhydride 1 aus Phosphor-, Phosphon- und Phosphinsauren einerseits und Methansulfonsaure, Trifluormethansulfonsaure und Schwefelsaure-monoimidazolid andererseits angepast werden. Fur die Reaktionen b) und c) konnten durch Tieftemperatur-FT-31P-NMR- Spektroskopie Phosphonium-Zwischenstufen nachgewiesen werden. Die Anhydride 1 lassen sich durch Umsetzen mit N-(Trimethylsilyl)imidazol leicht in Imidazolide 4 uberfuhren; diese Reaktion lauft uber zwei verschiedene Phosphonium-Zwischenstufen. Die Anhydride 1 wirken gegenuber neutralen oder schwach basischen Nucleophilen als Phosphorylierungsmittel.

The reaction of a trialkyl phosphite with trimethylsilyl iodide, which leads to O -trimethylsilyl esters of alkylphosphonic acid, has been shown to involve several steps, all of which are defined. The first step is the formation of the iodophosphite, involving a four centre mechanism in which P III plays the role of electrophile. This is in contrast to the analogous reaction of phosphates with alkyl halides (the Arbuzov reaction) which begins with nucleophilic attack of the phosphorus.

The reaction of triorganosilylsulfenyl halides R3SiSX (R  Ph, Et; X  Cl, Br) with carboncarbon double bonds, trialkyl phosphites, and organometallic reagents have been studied. With the first two nucleophiles the course of the reactions differed from that with organosulfenyl chlorides because of nucleophilic attack of halide ion on silyl group.

Stable ionic 11 adducts, thought to be of the type [(Me2N)3POSiMe3]+X− have been isolated from the interaction of HMPT with the halides Me3SiX (X  Br or I). Conductometric studies show that the equilibrium for formation of these adducts in CH2Cl2 lies well over to the products for X  Br or I, but for X  Cl the equilibrium lies close to the reactants. The known kinetic characteristics of reaction involving HMPT-catalysed racemisations or substitutions of silicon halides can be interpreted in terms of the formation of such phosphonium intermediates.

A study is described of the reaction of trimethylbromosilane and trimethyliodosilane with various esters of phosphorothioic and phosphoroselenoic acids of general structures (RO) 2 (RY)P=O (I) and (RO) 3 P=Y (II) (Y = S or Se, R = alkyl). The reaction results in replacement of the R groups by trimethylsilyl groups. No S -trimethylsilyl and Se -trimethylsilyl substituted esters were found among the products. Thus the displacement of the O -R group in II as well as the replacement of S -organyl or Se -organyl groups in I both lead to the corresponding O -trimethylsilyl isomer containing thiophosphoryl or selenophosphoryl groups. The following sequence of reactivity of the ester groups was observed: Download full-size image The process involves initially the reversible formation of a phosphonium salt intermediate in a fast step, followed by slow dealkylation. It was shown by low temperature 31 P FT-NMR studies that in the reaction of trimethyliodosilane with an ester bearing a P=O phosphoryl group, the equilibrium for the phosphonium salt formation lies well over towards the intermediate and so the intermediate can be observed directly. These mechanistic proposals were confirmed by conductance studies on the reaction system and by investigation of the stereochemical course of the corresponding reaction of an optically-active model thiophosphonate. In some cases the reaction of the halosilanes with the phosphates takes a selective course which allows the reaction to be used as a convenient route to O -silyl substituted esters of phosphorothioic or phosphoroselenoic acids.

In order to throw light on the possible role of positively charged tetra-coordinate silicon intermediates in the racemization of α-NpPhMeSiCl ( 1 ) induced by uncharged nucleophiles two sets of kinetic studies have been carried out. In the first the rates of two reactions namely racemization of 1 catalysed by (PhO) 2 (Me 3 SiO)PO ( 2 ) and transsilylation of 2 with 1 , which take place together and are believed to involve the same intermediate were determined; the transsilylation was found to be faster than the racemization, and involved transient formation of an optically active product. In the second the racemization of 1 catalysed by HMPT in various CCl 4 /CH 2 Cl 2 mixtures was studied; the rate was found to increase markedly with increase in the dielectric constant of the medium. The results of both sets of experiments were consistent with a mechanism involving a silyloxyphosphonium cation intermediate.

Die Synthese von Phosphorsaure-monoathylester, -diathylester und -triathylester (1–3) sowie von Phenylmethanphosphonsaure-monoathylester und -diathylester (4, 5) durch selektive Alkylierung der Orthophosphorsaure und Phenylmethanphosphonsaure mit Triathylphosphit wird beschrieben. Selective Alkylation of Polybasic Phosphoric Acids with Trialkyl Phosphite The synthesis of mono-, di-, and triethyl phosphate (1–3) as well as of mono- and diethyl phenylmethane phosphonate (4, 5) by selective alkylation of orthophosphoric and phenylmethane phosphonic acid with triethyl phosphite is described.

Die Alkoholyse von (Thiophosphorigsaure-O-athylester)-(phosphorsaurediathylester)anhydrid fuhrt zu gemischten Thiophosphorigsaure-O.O-dialkylestern und Phosphorsaure-diathylester. Thiophosphorigsaure-O-athylester-O-butylester ist auch durch Umsetzung von Phosphorigsaure-athylester-butylesterchlorid mit Schwefelwasserstoff erhaltlich.

Phosphorsaure-dialkylester, Carbonsauren und Sulfonsauren lassen sich durch Umsetzung mit Tetraalkylestern des Phosphorsaure-phosphorigsaure-anhydrids phosphorylieren. In allen Fallen entstehen die Anhydride des Phosphorsaure-dialkylesters und Dialkylphosphit mit hoher Ausbeute.

Direct evidence by 31P-n.m.r. spectroscopy is presented for the formation of a five-co-ordinate intermediate in the Arbuzov reaction of tervalent phosphorus esters with elemental chlorine or elemental bromine and benzenesulphenyl chloride.

The ratio of desulphurisation to deoxygenation of oxophosphoranesulphenyl chlorides, >P(O)SCI, by trivalent phosphorus compounds depends on the nature of the PIII compounds and is accompanied by inversion of configuration at the chiral phosphorus atom of the sulphenyl chloride.

Trimethylhalogenosilanes Me3SiX (X=Cl,Br) are remarkably efficient activators in the reaction of P(III) amidites with nucleosides and other alcohols of biological interest to give P(III) esters in excellent yield. This activation is illustrated by synthesis of P(III) compounds containing a phosphorus-fluorine bond. Under specially chosen conditions the interaction between trimethylhalogenosilanes, 2'-deoxy-nucleosidylphosphoroamidites and nucleosides allows synthesis of 5'-phosphonate -linked deoxydinucleotides. 2,4-Dinitrophenol is an effective activator in “amidite” coupling.

Direct evidence by 31P-n.m.r. spectroscopy is presented for the formation of a five-co-ordinate intermediate in the Arbuzov reaction of tervalent phosphorus esters with elemental chlorine or elemental bromine and benzenesulphenyl chloride.

Triethyl phosphite and elemental iodine in solution give transient iodotriethyl-phosphonium iodide which eliminates ethyl iodide to form diethyl phosphoroiodidate. An examination of the 31 P NMR and IR spectra over the temperature range −100° − 0°C fails to disclose any evidence for triethoxydi-iodophosphorane, contrary to a previous claim.

Organophosphorus acids and dithioacids are transformed in almost quantitative yield into the corresponding fluoridates by reaction with thionyl fluoride under very mild conditions.

Deselenisation of the optically active monoselenoacids lead to disubstituted phosphine oxides with high optical yield and the reaction provides a means of correlating chiral phosphorus monoselenoacids with their sulphur analogues.