Phosphonothioates, synthesis

Representative examples include the synthesis of phosphonothioic acids for evaluation as inhibitors of protein tyrosine phosphatases (equation 115)158. 

A less common approach to the synthesis of phosphinates is the reaction of electrophilic phosphonates with carbon nucleophiles such as Grignard reagents or lithium enolates. For example, the phosphinic acid analogue 71 of the amino acid statine was synthesized by displacement of tert-butyl lithioacetate on a 5-phenyl phosphonothioate 70 (Scheme 23)d104l The racemic diastereomers of the 5-phenyl phosphonothioate were obtained in pure form, and the displacement of the phenylsulfanyl moiety was found to be stereospecific, although the stereocenter at phosphorus would later be lost on hydrolysis of the ester. A similar displacement reaction has been described using the p h osp h on och I ori d ate.1711... 

A method for the simple synthesis of phosphonothioates (310) or phospho-nothioic acids (311) has been reported. It uses standard reagents and should be applicable to the preparation of phosphonothioic acids bearing a range of functional groups (Scheme 81). ... 

Menthyl phosphinates, in addition to being useful precursors for the synthesis of optically active tertiary phosphine oxides 5), phosphinamides ),and phosphonothioates were found to exhibit pmr spectra which are a rich lode of structural information. For menthyl n-alkylphenylphosphinates (8) the upfield portion of the pmr spectra features the three methyl doublets of the menthyl moiety. Chemical shifts of these signals for diastereomers... 

Petrov, K.A., Raksha, M.A., and Le Dong, H., Synthesis and study of the properties of alkenephos-phonic derivatives. Part 6. [2-Chloro- and 2-alkyl-2-(alkylthio)vinyl]phosphonic and -phosphonothioic diesters, Zh. Obshch. Khim., 46, 1991, 1976 J. Gen. Chem. USSR (Engl. Transl.), 46, 1918, 1976. 

Piettre, S.R., Simple and efficient synthesis of 2,2-disubstituted-1,1-difluorophosphonates and phosphonothioates. Tetrahedron Lett., 37, 2233, 1996. 

The nucleosidyl-3 -methylfluoridophosphonates (67) and (68) have been used for the synthesis of the corresponding methylphosphonate (69) and methyl-phosphonothioate (70) dimers respectively. The diastereomers (67) and (68) were prepared by phosphorylation of the corresponding 5 -protected nucleosides with (71) and for the latter mixture (68), separation of the individual diastereomers was possible using silica chromatography. Coupling of (67) and (68) with a 3 -0-protected nucleoside in the presence of DBU or sodium hydride gave over 95% yield of the respective dimers. 

In 1952, Kinnear and Perren recorded that the complex from EtCl, AICI3 and PCI3 was reactive to H2S at 130 °C and afforded a substance with the composition EtPS2- This reaction received further attention from Newallis et and was developed as a general method of synthesis in its essentials, the synthesis involves the formation of the dichlorides, RP(S)Cl2, which, in the absence of an acid acceptor, react slowly with H2S even at 160 °C in the presence of Et3N, the reactions are much faster (Scheme 56). Indeed, Grishina and coworkers and also Fukuto s group prepared the same products directly from phosphonothioic dichlorides and H2S. 

Also of potential value in synthesis is the halogenolysis process when, depending on reagent (CI2, S02,Cl2, PCI5, SCI2 or S2CI2) and conditions, either phosphonothioic dihalides, RP(S)Cl2. or, tetrahalophosphoranes RPX4 are formed. The action of sulphur... 

The synthesis of dimers containing phosphoroselonate internucleoside linkages has been described by Stawinski and Thelin. Selenisation of H-phosphonate diesters or H-phosphonothioate diesters is accomplished using a selenium transfer reagent 3H-1,2-benzothiaselenol-3-one (117). 

Stadlbauer and co-workers have developed a facile synthesis of carba-boranediyl-bis(glycophosphonates) (281, 283, 285) and corresponding phosphonothioates with one and two galactosyl moieties at the phosphorus atoms. These compounds showed high water solubility and low cytotoxicity even in millimolar concentrations. 

The formation of mixed anhydrides 2 is critical for overall yield of the conversion of H-phosphonate monoesters 1 into H-phosphonothioate 4. The transformation of an H-phos-phonate into an H-phosphonothioate function in the ribo series proved to be a stereoselective process. In contradistinction to (his transformation, synthesis of the ribonucleoside 3 -H-phosphonothioate via phosphinate intermediates [202] hardly showed any stereoselectivity. 

K.A. Petrov et al., Methods of synthesis of aryl phosphonothioic acids-, Russ. Chem. Revs., 55,1042,... 

The enantioselective synthesis of phosphonothioate (146) and fluoromethylene phosphonate (147) analogues of cyclic phosphatidic acid, the novel antagonists of lysophosphatidic acid receptors, has been presented. Synthesis of difluoromethy-lene analogue of sphingomyelin (148) in optically active form as a new sphingomyelinase inhibitor has been achieved. The synthesis and biological evaluation of 9-(5, 5 -difluoro-5 -phosphonopentyl)guanine derivatives (149), for use as a purine nucleoside phosphorylase inhibitor, has been described. 

The synthesis of novel enantiomerically pure C3-symmetric trialkanolamine ligand containing phosphoryl groups (211) involved opening the epoxide ring in diethyl 2,3-epoxypropylphosphonate with benzhydrylamine and benzylamine catalyzed by Cu2l2- Enantiopure O-ethyl (2-naphthyl)phosphonothioic acid shows excellent chiral recognition of racemic 1-phenylethylamine derivatives. ... 

As regards the modification of intemucleosidic links, bis(deoxynucleosidyl)-trimethylsilyl phosphites 190 can be converted to phosphorofluoridates 191 by the use of S02C1F,230 and dibenzoyltetrasulfide has been advocated as a rapid sulfur transfer agent in the synthesis of nucleoside phosphorothioates, being used to prepare a phosphorothioate after each cycle of a phosphoramidite synthesis.231 Oxidation of intemucleosidic H-phosphonothioates (2 -deoxy series) with iodine in aqueous acetonitrile in the presence of trimethylamine gives... 

In the area of 3, 5 -cyclic nucleotides, it has been found that attempted 5 -phosphorylation of the 3 -epimers of thymidine and deoxyadenosine with phosphoryl chloride gave the cyclic phosphates 195 (B = Ad, T) the 5 -phosphates could be obtained by phosphorylation of the 3 -0-benzoyl derivatives.245 Two groups have reported the synthesis of base-modified derivatives of c AMP (e.g. benzimidazoles, benzotriazoles, indazoles), for evaluation as activators of cAMP-dependcnt protein kinase 1.246,247 There have been syntheses described of ribonucleoside 3 ,5 -cyclic methyl- and phenyl-phosphonates248,249 and -phosphonothioates, one of the procedures giving both the cyclic phosphonates and phosphonothioates as the 5p-epimer only.249 a paper... 

Phosphonates and phosphonothioates which are separated from the ortto-carborane core by a methylene bridge were also reported. In these compounds, the electronic influence of the carbo-rane on the phosphonate group is low. Their synthesis starts from the Grignaid reagent (l-bromomagnesiomethyl)-ort/io-carborane and diethyl chlorophosphite (Scheme 2.3). Transformation into phosphonates 3 and 4 as well as into phosphonothioate 5 was achieved in the same manner as reported for the above-mentioned carborane derivatives. 

SCHEME 2.9 Synthesis of carboranediyl bis(phosphonate) 62 and bis(phosphonothioate) 63. (Adapted from Stadlbauer, S. Welzel, P. Hey-Hawkins, E. 2009. Inorg. Chem. 48 5005-5010 Stadlbauer, S. et al. 2009. Eur. J. Org. Chem. 6301-6310 Stadlbauer, S. 2008. Glycophosphonsauiekonjugate von Carbaboranen-Synthese und biologische Aktivitat. Doctoral thesis, Universitat Leipzig.)... 

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