Regioselective derivatization of ouabain with trialkylsilyl reagents and selective oxidation of the unprotected alcohols

Abstract Many mammalian tissues contain cardiac glycoside-like steroids that inhibit the sodium pump. A ouabain-like compound has been described in the human circulation and suggested to be ouabain or a closely related isomer. Ouabain is a highly hydroxylated compound and one of the most potent inhibitors of the sodium pump. Trialkylsilyl derivatization of ouabain has been carried out to determine reagent selectivity among the eight hydroxy groups as a prelude to the synthesis of regiospecific isomers. Mono-, di-, tri-, and hexa-trialkylsilyl derivatives have been prepared with substitution at the 19-, the 3′,19-, the 1,3′,19-, and the 1,2′,3′,4′,11,19-positions, respectively. Mass spectrometry and NMR confirmed the substitutions. Selective protection of the hydroxy groups allows selective oxidation of the unprotected steroid ring alcohols without oxidation of the 2′- and 4′-rhamnoside alcohols. Pyridinium dichromate oxidation of the di-trialkylsilyl and tri-trialkylsilyl derivatives gave the 1,11-diketone and the 11-ketone analogues, respectively. These regioselective reactions open a route to the synthesis of a series of closely related isomers of ouabain and other derivatives that may have useful structure-activity relationships and utility in the elucidation of the biosynthesis of ouabain-like compounds.