(Z)-6,9-epoxynon-5-enoic acid: a simple model which mimics the unusual hydrolytic lability of prostacyclin

Abstract

Evidence supporting the hypothesis that hydrolysis of the vinyl ether group of prostacyclin, accelerated by its carboxylic acid function operating in the carboxylate form, is responsible for the unusual hydrolytic lability of this substance is provided by the remarkably similar behaviour of (Z)-6,9-epoxynon-5-enoic acid; the latter is a simple model of prostacyclin which contains all of the structural features needed for this destabilization mechanism to function.

The Intramolecular Asymmetric Pauson−Khand Cyclization as a Novel and General Stereoselective Route to Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil)

“…From a chemical viewpoint one can readily understand the hydrolytic lability of PGI 2 on the basis of the presence of the Z -vinyl ether group. Protonation of 1 yields the oxonium ion 2 followed by ring opening of the derived hemiketal to yield 6-keto-PGF 1 α ( 3 ) 7a. Additional driving force for the rapid hydrolysis has been proposed to involve the carboxylate form of 2 4 and proven in an elegant kinetic study 7b…”

“…Protonation of 1 yields the oxonium ion 2 followed by ring opening of the derived hemiketal to yield 6-keto-PGF 1 α ( 3 ) 7a. Additional driving force for the rapid hydrolysis has been proposed to involve the carboxylate form of 2 4 and proven in an elegant kinetic study 7b …”