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

• Published in: Tetrahedron Vol. 69; no. 52; pp. 11109 - 11115
• Main Authors: Korshin, Edward E., Pozdeev, Oskar K.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 30.12.2013; Elsevier
• Subjects: Antiviral activity; Bearing; Bonding; Chemistry; Chemistry, Organic; Domino reactions; Formations; Hydrolysis; Hydrophosphonylation; Influenza; Ketones; One-pot synthesis; Physical Sciences; Science & Technology; Synthesis; Tetrahedrons; One-pot synthesis; Hydrophosphonylation; Domino reactions; Ketones; Antiviral activity; ASYMMETRIC-SYNTHESIS; CATALYZED HYDROPHOSPHONYLATION; ENANTIOSELECTIVE SYNTHESIS; NUCLEOSIDE ANALOGS; EFFICIENT SYNTHESIS; BROOK REARRANGEMENT; POTASSIUM FLUORIDE; DIALKYL PHOSPHITES; ADDITION-REACTIONS; ALPHA-HYDROXY PHOSPHONATES
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2013.11.007

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. [Display omitted]