Phosphonic acid analogs of GABA through reductive dealkylation of phosphonic diesters with lithium trialkylborohydrides

Lithium trialkylborohydrides were found to mono-dealkylate dialkylphosphonates rapidly (rate of cleavage Me, Bn > 1°). The reaction was applied to the synthesis of a new GABA C antagonist, 2-aminoethyl methylphosphonate ( 4a). Lithium trialkylborohydrides were found to effect rapid monodealkylation of phosphonic diesters, and this reaction was applied to the synthesis of alkylphosphonic acid 2-aminoethyl esters [H 2N(CH 2) 2OP(OH)R, 4], a little-explored class of analogs of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Compound 4a (R = Me) proved to be a potent antagonist at human ρ1 GABA C receptors (expressed in Xenopus laevis oocytes), with an IC 50 of 11.1 μM, but is inactive at α 1β 2γ 2 GABA A receptors.