Azido phosphonate

The formation of flve-membered cyclic imines through a Staudinger/intramolecular aza-Wittig reaction can also be performed by solid-phase synthesis and has been applied for the first synthesis of lanopylin Bi (108). The total synthesis, which takes only four steps, starts with a phase-transfer alkylation of diethyl 2-oxopropylphosphonate 105 with a 2-iodoethyl azide, affording the azido phosphonate 106, which undergoes a phase-transfer Homer-Emmons Wittig reaction with heptadecanal to provide the azido enone 107. An intramolecular aza-Wittig reaction of the enone 107 with polymer-supported triphenylphosphine in toluene completed the first total synthesis of lanopylin Bi (108) in 76% yield (Scheme 15.22). 

Azido-3 -deoxythymidine 5 -[(methyl 5-acetamido-3,5-dideoxy-D-g/ycero-a-D-ga/acto-non-2-ulopyranosylonate) phosphonate]... 

The nucleophilic addition of NaN3 leads to 2-azido-2-alkenyl phosphonates 145, which would react further with PPh3 to afford phosphinimine 147. The migration of the C=C bond in 145 was not observed. Upon photolysis, 145 can also cydize to afford azirine 146 (Scheme 10.71) [76]. 

It has been shown that coupling of the ethyl phosphinate A with 5 -azido-2 -methoxy-5 -deoxythymidine B to afford the corresponding phosphon-amidate proceeds with retention of configuration at the phosphorus atom. Determine the configuration of reactants and product. 

Enzymatic alcoholysis of 3-chloro-2-chloroacetoxy, 3-azido-2-chloroacetoxy and l-chloro-2-chloroacetoxypropyl phosphonates (285), (286) and (287) catalysed by immobilized mucor miehei lipase (IM) and Candida antarectica lipase B was a particularly effective method for the formation of the corresponding highly enriched enantiomerically chloroacetoxyphosphonates (288), (289) and (290). Kinetic resolution by specially selected reaction sequences led to phosphocarnitine (291), phosphogabob (292) and phosphomycin (293) respectively (Scheme 73). ... 

The S-pivaloyl-2-thioethyl 5-fluorophosphate derivative of 3 -azido-3 -deoxy-thymidine (24) was synthesised by Perigaud and evaluated for anti-HIV activity in an attempt to improve the biological activity of the mononucleoside 5 -fluorophosphate parent. The fluorophosphotriester was obtained by treating the H-phosphonate diester in pyridine with iodine and triethylamine trihydrofluor-ide. ... 

A chemoenzymatic synthesis of the P-a-methyl 2 -deoxynucleoside triphosphates 122 has been described which involves reaction of the 5 -0-(methylpho-sphonyl)-N-protected nucleosides with pyrophosphate in the presence of CDI. Removal of the base protection by treatment with penicillin amidase gave compounds 122 leaving the labile a-methylphosphonate intact. A number of 2 -deoxythymidine 5 -triphosphate and 3 -azido-2, 3 -dideoxythymidine 5 -tripho-sphate analogues (123) containing a hydrophobic phosphonate group have also been synthesised and evaluated as substrates for several viral and mammalian polymerases. Some y-ester (124) and y-amide (125) derivatives of dTTP and 3 -azido-2, 3 -dideoxythymidine 5 -triphosphate (AZTTP) were also synthesized and studied. The y-phenylphosphonate triphosphate 126 and its conjugation to biotin and fluorescein labels has also been described. 

Ohler, E., and Kotzinger, S., Synthesis of (3-amino-l-alkenyl)phosphonic acids from allylic a- and y-hydroxyphosphonates. Sigmatropic reanangement of dialkyl (l-azido-2-alkenyl)phosphonates, Liebigs Ann. Chem., 269, 1993. 

Treatment of the carbanions from P-alkyl analogues of compound 336 with 2,4,6-tri-isopropylbenzenesulphonyl azide yields the azides (397) diastereoselectively acidolytic removal of the 1,3,2-diazaphospholidine ring and catalytic reduction of the azido group affords (l-aminoalkyl)phosphonic acids of known chirality. ... 

The relevant chemistry of the azido group is also mainly connected with its reduction to amino (Chapter 4, Section IV.C. 1. f), but the 1,3-dipolar cycloaddition of azidoalkyl phosphonic diesters 239 to acetylenes is also of some importance with regard to the synthesis of phosphinoylated 1,2,3-triazoles, and will be considered further (Section IV.D). 

Chlorination of dialkylphosphites with NCS affords the corresponding dialkylchlorophosphate. The dialkylchlorophosphates generated react with alcohols to give phosphonate esters. The direct chlorination of dihenzylphosphite with NCS was used in the synthesis of phosphate prodrugs of the anti-HIV drug 3 -azido-2, 3 -dideoxythymidine (AZT) (eq 32). ... 

The fused 1,2,3-triazolino-pyrrolidine 84 was obtained by oxidation of 2,3,4-tri-0-acetyl-5-azido-5-deoxy-D-xylose dibenzyl dithioacetal with MCPBA, the reaction involving intramolecular dipolar cycloaddition of the azido group onto a 1,2-double bond formed by loss of acetic acid. A similar product was obtained from the D-rt o-analogue. Nucleotide analogues based on hexenopyranosyl phosphonic acid derivatives with a nucleoside base moiety linked at C-4 are covered in Chapters 9 (Section 2.6) and 17. 

In this context, Alvarez et al. synthesized a boranophosphinate 18, analogue of AZT (Scheme 2) [22]. The formation of the phosphorus-boron motif required six steps, starting from the stable thymine phosphonate 14. A full reduction by lithium aluminium hydride followed by partial oxidation mediated by hydrogen peroxide afforded the //-phosphinic acid 16. After the introduction of the azide group, azido-//-phosphinate 17 undergoes a borylation and desilylation to yield to the boranophosphinate 18. 

Azido-2, 3 -dideoxythymidine-5 -H-phosphonate was obtained by reacting 3 -azido-2, 3 -deoxythymidine with PCI3 and subseqnent hydrolysis (see Appendix) [184-186]. 

General procedure for the immobilization of 3 -azido-2,3 -dideoxythymidine onto polyioxyethylene H-phosphonate)s... 

Dichloroethane (5 mL), carbon tetrachloride (15 mL), triethylamine (2 mL), acetonitrile (7 tnL), and 3 -azido-2,3 -dideoxythymidine (250 mg, 0.94 nunol) were placed in a threenecked flask equipped with magnetic stirrer, reflux condenser, dropping funnel, and inert-gas outlet. A solution of poly(oxyethylene H-phosphonate) (232 mg, 0.94 nunol of repealing units) in dichloroethane (5 mL) was added dropwise at ambient temperature under continuous stirring. The reaction was allowed to proceed for 24 h. After filtration of the precipitated triethylamine hydrochloride, the filtrate was concentrated and the polymer conjugate was precipitated by addition of diethyl ether. The isolated product was dried at 35-40 under reduced pressure (10 mbar). The elemental analysis of chlorine showed a trace of CI2. Yield was 485 mg (100%). 

A number of H-phosphonate derivatives of 3 -azido-2, 3 -dideoxynucleosides with adenine, guanine, and cytosine [59,63-65] exhibit antiviral acivities with selectivity similar to or higher than that of the corresponding nucleoside. 

Unfortunately, charged phosphorylated or phosphonylated nucleosides are unable to penetrate the cell membranes or the blood-brain barrier because of their low lipophiUci-ty. Meier et al. [66] have described the synthesis of a new prodrug system for antiviral nucleosides AZT and ddT based on a-hydroxybenzylphosphonates 1, which present uncharged prodrugs of 5 -nucleoside H-phosphonates and 5 -nucleoside monophosphates. All compounds 1 exhibited pronounced activity against HIV-l- and HlV-2-infected cells without toxicity. Compounds 3 can be considerd as potential prodrugs of the 3 -azido-3 -deoxythimidine and 2, 3 -deoxythimidine, their H-phosphonate monoesters as well as their monophosphates. 

DNA and RNA fragments. The 5 -hydrogen phosphonate-3 -azido-2, 3 -dideoxythymi-dine is one of the most significant anti-HIV prodrugs, which is currently in clinical trials. 

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