Phosphonate esters, Mitsunobu reactions

Formation of the phosphonate-nucleoside ester bond using the Mitsunobu reaction [109,110]. 

Amino-l-hydroxyethyl)phosphonic acid occurs in the plasma membrane of Acanthamoeba castellani and the 2R isomer is formed, in that organism, by the hydroxy-lation of (2-aminoethvl)phosphonic acid This biosynthesis step in vitro has been studied by Hammerschmidt" who synthesized various chiral deuterium-labelled derivatives of both compounds using the isotopically labelled 2-benzyloxyethanal in Abramov reactions to obtain, initially, the dimethyl (2-benzyloxy-l-hydroxyethyl)phosphonate (362). This ester was resolved through the diastereoisomeric carbamates 363 the separated carbamates were sequentially de-l-O-protected, silylated at the a-HO group, debenzylat-ed and, by means of the Mitsunobu reaction, converted into dimethyl [2-eizido- -(tert-butyldimethylsilyloxy)ethyl]phosphonates. Subsequently, standard reactions were used to transform the latter into the diastereoisomeric, isotopically labelled (2-amino-1-hydroxy-ethyl)phosphonic acid. 

Direct esterification of a labile alko)yamine (312) has been achieved by the Mitsunobu reaction or a nucleophilic substitution. Thus, corresponding phosphonic ester derivatives (313) and (314) have been obtained under smooth conditions (Scheme 104). ... 

Although this group of compounds is, as yet, very poorly represented, at least three routes for their synthesis already exist. The reactions between acethydroximic acids and (haloalkyl)phosphonic diesters yield the O-derivatives 372, from which selective work-up steps (Scheme 53) lead to the esters 373 or to the free [(aminooxy)alkyl]phosphonic acids 37 580 conventional approach consists in the reaction between a (1-hydroxyalky 1)-phosphonic or -phosphinic diester with A-hydroxyphthalimide in the presence of diethyl azodicarboxylate and PhjP under Mitsunobu conditions the resultant [l-(phthal-imidooxy)alkyl] acicl diesters lose the phthalimido group on hydrazinolysis, and a final aci-dolysis provides the [l-(aminooxy)alkyl]-phosphonic or -phosphinic acids. 

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