Total Synthesis of (15R)- and (15S)-Prostaglandin A2.

Abstract

From both pharmaceutical and structural perspectives, the large family of prostaglandins represent a truly remarkable class of natural products. Prostaglandin A2 is a tissue hormone naturally found in human seminal plasma and in the sea whip Plexaura homomalla with yet poorly understood biological or therapeutic effects. Herein, a novel strategy for the stereoselective construction of both naturally occurring prostaglandin A2 epimers and first insights into their functional effects on the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) type A receptors (GABAAR) are provided. The synthesis of both epimers was achieved in only 11 steps starting from commercially available 2,5-dimethoxy-tetrahydrofuran employing an organocatalytic domino-aldol reaction, a Mizoroki-Heck reaction, a Wittig reaction as well as an oxidation-decarboxylation sequence. The (15R)-epimer significantly reduced GABA-induced currents through GABAA receptors while its (15S)-epimer did not show any significant effect. These data suggest that (15R)-PGA2 might serve as a novel scaffold for the development of selective GABAA receptor modulators.