Phosphites 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. 

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 ... 

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... 

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). 

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... 

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

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). 

The phosphitylation procedure activated by tetrazole led to the phosphite structure (step a) which was effectively oxidized by TBHP to yield the corresponding phosphate (step b). Finally all 2-cyanoethyl protecting group were removed by the action of DBU in the presence of the silylating reagent bis(trimethylsilyl)acetamide BSA (step c). The latter is indispensable to secure total deprotection. 

First phosphitylation was performed by 0-benzyl-bis(iV,iV,-diisopropyl)-phosphoroamidite in the presence of diisopropyl-ammonium tetrazolide at room temperature in dichloromethane solution (step a). The intermediate phosphoroamidite was coupled with a glycerol moiety in the presence of tetrazole in boiling CH2CI2 to give the benzyl phosphite (step b), which was oxidized by CPBA in CH2CI2 into the corresponding phosphate (step c). In the final step d total debenzylation was achieved by Pd/C transfer hydrogenol-ysis in the presence of formic acid and methanol at room temperature. 

The coupling led to the intermediate phosphite (step a) which was oxidized by TBHP (step b). The phosphate formed containing eight ethoxy groups was deprotected by trans-esterification using trimethylbromosilane and subsequent hydrolysis by water (step c). Two benzoyl groups were removed by basic hydrolysis (step d). The same tetrakis phosphate was prepared by phosphitylation with dibenzyl-h/,iSr-diisopropylphosphoroamidite in the presence of tetrazole (step c) followed by oxidation with CPBA (step f). The removal of all benzyl and benzoyl groups was achieved in one step by sodium in liquid ammonia (step g). 

Polynucleotides. These compounds are now generally prepared by use of a bifunctional phosphitylating agent such as o-chlorophenylphosphorodichloridite (6, 114-115) or methoxydichlorophosphine, CHjOPCl,. The intermediate nucleoside phosphites from these reagents tend to be unstable. This difficulty can be alleviated by use of I, which reacts with suitably protected nucleosides to form stable phosphoramidales 2 in good yield. These products can be activated for formation of a dinucleotide phosphite (4) by treatment with a weak acid such as N,N-dimethylaniline hydrochloride or l/Z-tetrazole (5). 

Polystyrene loaded with cyanoethoxy N,N-diisopropylamine phosphine 35 has turned out to be a versatile and mild phosphitylating agent (Scheme 15) [41]. The intermediate phosphite triester 36 was oxidized and the cyanoethoxy group was removed using DBU followed... 

A synthetic approach to /3-sultams containing a direct bond between a tri- or tetracoordinated phosphorus atom and the nitrogen atom of the 1,2-thiazetidine 1,1-dioxide ring has been realized by direct phosphitylation or phosphorylation at nitrogen. Unfortunately, attempts to synthesize N-phosphorylated /3-sultams by reaction with diethyl phosphorochloridate and diethyl phosphorobromidate, generated in situ from diethyl phosphate and carbon tetrachloride or carbon tetrabromide, failed. However, when the /3-sultam is treated with freshly distilled diethyl phosphorochloridite or tetramethylphosphorodiamidous chloride in the presence of triethylamine, the expected AHliethy I phosphite and iV-phosphorodiamidous /3-sultams 150 are obtained (Equation 10). /3-Sultams unsubstituted... 

The first synthesis of a dinucleotide analogue combining phosphorothioate and boranophosphate features has been reported. To prepare dithymidine boranophosphorothioate (71), Fmoc-protected thymidine was phosphitylated by bis(diisopropylamino)-chlorophosphine in the presence of DMAP. The resulting phosphoramidite was treated in situ with a 3 -protected thymidine and tetrazole and was then converted to a phosphite triester with nitrophenol. The phosphite triester was subsequently treated with BH3-SMe2 followed by LiS2 in the presence of 18-crown-6 to yield (71). This novel type of dinucleoside... 

Phosphitylation of 8-bromo-2, 3 -0-isopropylideneadenosine with diethyl phosphorochloridite and triethylamine followed by irradiation of the resultant phosphite triester in acetonitrile affords (111) as a mixture of diastereoisomers which on deprotection gives P/ 5 -anhydroadenosine-8-phosphonic acid. The mechanism proposed involves homolytic fission of the carbon-bromine bond followed by attack on the phosphite by the C-8 radical. 

The second phosphorylation methodology which involves phosphitylation using phosphoramidites 21 such as dibenzyl N,N-diisopropylphosphoramidite (22)17 and its cyclic analogue 23 (XEPA)- - and subsequent oxidation of the resultant phosphite intermediate 24 may provide a more general method for... 

The phosphitylation of a ketone through its enol form leads to the phosphorus(III) esters carrying a conjugated unsaturated carbonyl moiety their isomerization to the phosphonic diesters 603 (R = EtO) occurs reasonably readily, but other compounds in which, for example, R2P = (Pr 0)(Et2N)P, isomerize with greater difficulty, during distillation, or during an extended period at room temperature ". Other phosphite esters, 604, isomerize when heated at 160 or in the presence of a trace of metallic sodium at the same tem-perature. The formation of dialkyl (4-oxopentyl)phosphonates by similar means has also been reported. ... 

When the reaction is carried out in the presence of a trace of a Lewis acid, e.g. FeCl3, the phosphitylation of an a-hydroxyketone, e.g. benzoin, leads not to a phosphite ester, but to a (2-oxoalkyl)phosphonic diester there appears to be, as yet, little information on the scope of this procedure ... 

In a search for tervalent phosphorus acid derivatives with better phosphitylation properties than usual aminophosphines or phosphoramidites Nifant ev et al. have prepared several new reagents. These include pyrazole derivatives, e.g. (51), 2-aminopyridine derivatives, e.g. (52), amidine derivatives, e.g. (53), and hydrazine derivatives, e.g. (54). They were prepared by standard methods and examined for their reactivity towards alcohols and, in the case of the amidine derivatives, for their tendency to isomerize by migration of the phosphorus group to the other nitrogen atom. Another type of reactive tervalent phosphorus acid derivative is phosphites derived from hydroxylamine. Several stable derivatives, e.g. (55) and (56), have been prepared and substitution reactions with alcohols studied. ... 

Figure 8.3 Process of solid-phase phosphoramidite nucleotide synthesis. In the process, X = linker which is later incorporated into the polymer matrix DMTr = dimethoxy trityl protecting group which is removed by treatment with add to hberate the hydroxyl gronp for snbseqnent phosphitylation reaction. B s = protected purine and pyrimidine bases. Phosphite is oxidized with iodine in the presence of esterification agent to phosphotriester before the chain extension or it is oxidized at the completion of chain extension as shown...

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