Phosphitylating reagent

Another convenient phosphitylating reagent for use in an oligodeoxyribonucleotide synthesis based on the phosphoramidite approach is bis(tetrazolyl)morpholinophosphine. This is generally prepared in situ from morpholinophosphordichloridite containing di-isopropylethylamine and two equivalents of tetrazole in dichloromethane/pyridine at... 

Unreacted support-bound nucleoside hydroxy groups can be blocked with diethoxy-triazolylphosphine. Oxidation of the phosphite triester to phosphate triester was achieved by I2. Yields in the condensation exceeded 95%. Tetrazolide as phosphitylating reagent is superior to a 4-nitroimidazolide, a triazolide, or even a chloride.11061... 

Another effective synthesis of a nucleosidephosphoramidite takes advantage of condensation of the phosphitylating reagent 2 -cyanoethoxy(A V-diisopropyl)amino-3-nitro-l,2,4-triazolylphosphine with 5 -dimethoxytritylthymidine.[ 1081... 

Keywords Phosphitylating reagents Phosphites Bioconjugates Phosphoroamidites P-chiralbiophosphates analogues Phosphorofluoridites... 

In contrast to tetracoordinate phosphorus compounds which are involved in the mechanism of life or are related to biophosphates, tricoordinate phosphorus compounds have not been found in nature. However, their importance in the synthesis of biophosphates is very great. The introduction of P compounds as phosphitylation reagents was a turning point in synthetic biophosphate chemistry. 

Example 9 a noteworthy example is the activation of bis(4-nitrophenyl)-iV,N-diisopropylphosphoroamidite [31] in coupling with alcohols activated by TMCS. This difunctional phosphitylating reagent does not react with alcohols in the presence of tetrazole, but in the presence of TMCS such a coupling becomes possible [37a,bj. 

Example 18 Shuto et al. have prepared 3,7-anhydro-D-glycero-D-ido-octi-tol 1,5,6-trisphosphate as a novel IP3 receptor ligand employing 0-xylene-AT,N-diethylphosphoroamidite (XEPA) as phosphitylating reagent [46], [47a,bj. The coupling was performed in the presence of tetrazole (step a). Oxidation of the phosphite by m-chloroperbenzoic acid (CPBA) afforded the corresponding phosphate (step b). 

Example 19 Crich and Dudkin have used phosphoroamidite containing two different protecting groups 0-benzyl-0-2-cyanoethyl-iV,Ar-diisopropyl-phosphoroamidite [48]. This phosphitylating reagent was prepared in excellent yield from 2-cyanoethyl NyN diisopropylchlorophosphoroamidite, which was immediately used for coupling with an appropriate alcohol in the presence of tetrazole and oxidized without delay with TBHP. This kind of phosphorylation procedure was used in the synthesis of 4,8,12,16,20-pen-tamethyl-pentacosylphosphoryl / -o-mannopyranoside, an unusual / -man-nosyl phosphoisoprenoid from Mycobacterium avium. 

Example 24 preparation of an asymmetrically-protected phospho-roamidite 0-tert-butyl-0-2-cyanoethyl-iV,iSr-diisopropylphosphoroamidite as a phosphitylating reagent in the synthesis of phosphopeptides has been described by Toth s group. [52]. This reagent allows the efficient synthesis of serine and threoine containing phosphopeptides by the global approach. 

The phosphitylation reaction (step a) and sulfurization leading to the corresponding thiophosphate (step b) proceeded under standard conditions. After deprotection (step c) and selective introduction of the DMTr group (step d) no transphosphorylation 2 3 was noted. This fact can be explained by the steric factor combined with the lower activity of thiophos-phates in comparison with normal phosphates. This enabled further phosphitylation (step e) by the customary phosphoroamidites. A difficulty in Se-kine s procedure is that the phosphitylating reagent must be prepared in situ and has relatively low purity. Luckily the by-products formed are inert tetra-coordinate species. 

Example 29 iV,Ar-diisopropyl-bis[(trimethylsilyl)ethyl]phosphoroamidite have been prepared from commercial available dichloro(diisopropy-lamino)phosphine and 2-(trimethylsilyl)-ethanol [60] in 65% yield after purification by chromatography. Chao et al. have used this phosphitylating reagent in a way which is compatible with the Fmoc/tcrt-butyl strategy for the synthesis of phosphotyrosine containing peptides [61]. 

The use of 2-cyano-l-f-butylethyl- and 2-cyano-l-(l,l-diethyl-3-butenyl)ethyl-phosphorimidazolidite as new phosphitylating reagents has been reported for... 

The use of benzyl A-phosphonate (Fig. 16, 37) was illustrated with the synthesis of a 5-mer phosphoserine-containing peptide [146]. The reagent was activated by pivaloyl chloride in pyridine, followed by in situ oxidation with 1% iodine (w/v) in pyridine-water (98 2 v/v). Phosphoramidites are considered to be superior to the other phosphitylating reagents and have been extensively used for the synthesis of peptides of significant functional complexity. Kitas et al. [104] did not observe differences in reactivity for phosphoramidites d, i-k (Table 2), but the use of this type of... 

Reproduced from Hardacre C, Huang H, James SL, Migaud ME, Norman SE Pitner WR. Overcoming hydrolytic sensitivity and low solubility of phosphitylation reagents by combining bnc liquids with mechanochemistry. Chem Commun 2011 47 5846-8, with permission from the Royal Society of Chemistry. 

Preparation of a Phosphitylation Reagent (12) for Nucleotide Synthesis. The phosphitylation reagent (12), useful for nucleotide synthesis, is readily prepared by reaction of (1) with phosphorus trichloride in acetonitrile (eq 7). ... 

Parang reported the preparation and use of the polymer bound mono-, di-, tri- and tetraphosphitylating reagents [50a-d]. These immobilised phosphitylating reagents could react with unprotected nucleosides in the... 

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