Phosphitylation/oxidation

Our premise for the selection of a phosphitylation/oxidation sequence derived from its successful application during the course of the Park nucleotide synthesis.14 Hitchcock reported the phosphitylation/oxidation of lactol 17, existing predominantly as the a-anomer, provided the desired a-phosphate, albeit with a modest 2.5 1 preference.15 In related work, the Walker group reported a similar phosphitylation/oxidation sequence applied to lactol 19 provided a-phosphate 20 as the exclusive product in very good chemical yield.16... 

Scheme 41.32 The first catalytic asymmetric phosphitylation/oxidation of an inositol derivative by Miller et at. (er = enantiomeric ratio).

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... 

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... 

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). 

A phosphitylation procedure was carried out in THF using tetrazole as the activator subsequent oxidation was performed by TBHP in THF (steps a and b). Simultaneous cleavage of 2-cyanoethyl and Fmoc groups was achieved by DBU in dichloromethane solution (step c). Finally the tert-butyl group was removed under acidic conditions by trifluoroacetic acid (TFA). In phosphitylation reactions leading to the phosphopeptides, symmetrically protected phosphoroamidites have formerly been used [53]. 

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). 

The phosphitylation procedure (step a) proceeds in the presence of EtN(i-Pr)2 (DPEA) and the subsequent oxidation by TBHP (step b). The cyclic phosphate is deprotected stepwise (steps c and d) and serves as a model for the physiological milieu . It has been possible to deliver phosphate monoesters via steps c and d in a controllable manner from cyclic phosphotri-esters at physiological pH. 

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... 

Oxidation of A-diethylphosphito to A-diethylphosphono derivatives 151 has been performed using 2-picoline A-oxide, MCPBA, diphenyl selenoxide, or 7-butyl hydroperoxide (TBHP). The latter was selected as the most efficient reagent. Similarly, the N-phosphitylated /3-sultams undergo reactions of oxidative addition of elemental sulfur and selenium giving 2-thio- and 2-selenophosphono /3-sultams 152 and 153, respectively, in satisfactory yields (Scheme 46) <1999HAC61>. 

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