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 A 2 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 A 2 epimers and first insights into their functional effects on the major inhibitory neurotransmitter γ‐aminobutyric acid (GABA) type A receptors (GABA A R) 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 (15 R )‐epimer significantly reduced GABA‐induced currents through GABA A receptors while its (15 S )‐epimer did not show any significant effect. These data suggest that (15 R )‐PGA 2 might serve as a novel scaffold for the development of selective GABA A receptor modulators.