Phosphitylation

The Mitsunobu conditions also can be used to effect a variety of other important and useful nucleophilic substitution reactions, such as conversion of alcohols to mixed phosphite esters.56 The active phosphitylating agent is believed to be a mixed phospho-ramidite. 

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... 

Phosphitylation with Azolides of Phosphorous Acid Synthesis of Oligonucleotides... 

The phosphitylation agent A-tetrazolyldiethoxyphosphine (phosphorous diester tetrazolide) can be made in situ from diethoxydiisopropylaminophosphine and two moles of tetrazole (tetrazole activation of phosphoramidites). 961... 

In the phosphite triester approach to the synthesis of nucleotides, morpholinophos-phorous ditetrazolide is used as the phosphitylating agent. The procedure generally consists of three steps ... 

Reaction of a 5 -0-protected nucleoside with moipholinophosphorous ditetrazolide (phosphitylation),... 

Similar phosphitylation and subsequent conversion to a dinucleotide has been carried out using the methyl- or m-chlorophenyl esters of a phosphorous acid bisazo-lide.[101H103]... 

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... 

A phosphitylation instead of an azole transfer occurred in the reaction of a guanosine derivative with phosphorous diester tetrazolide (diethoxytetrazolylphosphine) [2003,[2013... 

Thermal phosphitylation of methyl a-D-mannopyranoside (3) with P(NMe2)3 in pyridine or tetramethylurea gave 40% of a-methyl-D-mannopyranoside - 2,3,6-bicyclophosphite (4a). It underwent acetylation giving the corresponding acetate 4b sulfuration, and selenation afforded the corresponding pentavalent thio (4c) and seleno (4d) derivatives, respectively (Scheme 2). The trivalent acetate 4b was found to react with CuBr, Rh(CO)2(acac) and Cl2 [17]. 

Scheme 2 Phosphitylation of methyl (X-d-mannopyranoside (3) with P(NMe2)3...

A convenient route to j3-phosphorus nitroxides involves the 1,3-addition of trimethylsilyl phosphites (e.g., diethyl) or trimethylsilyl phosphines (e.g., diphenyl) to aldo nitrones (e.g., a-PBN, DMPO), or keto nitrones (e.g., 2-Et-DMPO or 2-Ph-DMPO), to form a-phosphityl- or a-phosphinyl-O-silylhydroxyl-amines. Acidic hydrolysis provides the corresponding hydroxylamines which are easily oxidized to p-phosphorus-nitroxides (690). 

Besides N-glycosyl triazoles, N-glycosyl tetrazoles were introduced by Sulikowski and coworkers [239]. N-Glycosyl tetrazoles were formed via phosphitylation of... 

The mild conditions offered by the approach of phosphitylation of the anomeric hemiacetals and subsequent oxidation of phosphites to phosphates suggest a very attractive alternative to the 1-0-lithiation method used in lipid A synthesis considering the complexity of the substrates. Indeed, an application of the phosphoramidite methodology was reported to be effective for the stereoselective instalment of the a-anomeric phosphate... 

The H-phosphonate approach entails phosphitylation of a hydroxylic component with an activated unprotected derivative of phosphonic acid to furnish H-phosphonate (a stable tetra-coordinate form of the unprotected monophosphite) followed by oxidation on phosphorus. The H-phosphonate approach is not generally used for the synthesis of monophosphates due to the difficulty of oxidation of the H-phosphonate monoesters and the necessity either to render the phosphorus atom of H-phosphonate into the three-coordinate form by silylation (to form disilylphosphite) or to introduce a protecting group (to form H-phosphonate diester) prior to oxidation. Nevertheless, in rare cases, the H-phosphonate procedure turns out to be a method of choice if, for instance, the simultaneous oxidation of functional groups other than H-phosphonate is required.51... 

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. 

Dabkowski et al [28] have found that 2,4-dinitrophenol (DNP), whose pKa=4.1 is close to that of tetrazole pKa 4.9, acts as an efficient activator of phosphate synthesis via the phosphoroamidite procedure. The reaction of amidites with an equivalent amount of nucleoside in the presence of 2,4-dinitrophenol proceeds in very high yield and at rates comparable or higher than those when tetrazole is used. Phosphitylations activated by 2,4-dinitrophenol (DNP) take place at room temperature in aprotic solvents like THE,... 

Example 7 the bis(2,4-dinitrophenyl)phosphoroamidite which can be prepared by a standard procedure reacts with alcohols in a non-selective way which leads to a mixture of products [28]. From a mechanistic point of view this result is consistent with spontaneous displacement of a 2,4-dinitro-phenoxy group in the reaction with alcohol which liberates free DNP. The latter activates the amino group allowing further ligand exchange. However if phosphitylation by the bis(2,4-dinitrophenyl)phosphoroamidite is performed in the presence of one equivalent of triethylamine, high chemoselec-tivity is observed, and the nucleoside (2,4-dinitrophenyl)phosphoramidite is formed in over 92% yield. 

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 20 diallyl-iV,N-diisopropylphosphoroamidite has been prepared by Bannwarth and Kiing and employed in the phosphitylation of the peptide hydroxy function [49]. The phosphitylation by this reagent proceeds in the presence of tetrazole (step a) followed by CBPA oxidation (step b) and removal of allyl protecting groups in the presence of Pd(0)P(C6H6)3 (step c). 

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. 

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