[1-Hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonates and -phosphinates: convenient synthesis through intramolecular Abramov reaction and protective activity against influenza A

A combination of intramolecularization and tandem reaction methodologies has been applied to the synthesis of diethylammonium[1-hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonates and -phosphinates, which were found to be unavailable through a standard intermolecular hydrophosphonylation/hydrolysis sequence. A mild hydrolysis of amidophosphites and -phosphonites, bearing 2-acetylphenoxy-fragment and a hydrolytically labile diethylamino-group at the same trivalent phosphorus atom, directly afforded the title compounds. The overall process probably consists of three steps: (i) selective hydrolysis of the P(III)-N bond to generate the hydrophosphoryl-type intermediates; (ii) formation of the strained 2-substituted 3-hydroxy-2-oxo-2,3-dihydro-1,2-benzoxaphospholes through intramolecular Abramov reaction; (iii) hydrolysis of the endocyclic P(IV)-O bond in the 1,2-benzoxaphospholes to give the acyclic products. Being only modestly active in vitro, at high dosage non-toxic water-soluble title α,γ-dihydroxyphosphonates and -phosphinates exhibited beneficial, but short-lasting effect against experimental influenza A infection (H3N2) in mice.