Synthesis of 15-Deoxy-12-hydroxy-10-(trifluoromethyl)-Δ⁷-PGA₁ Methyl Ester

Abstract

Cross-conjugated alkylidene prostaglandins have been shown to be potent cytostatic agents that exert their action through a unique and unusual mechanism. Compounds in this class also inhibit viral replication and have a role in osteogenesis and adipogenesis; consequently, they are of considerable current interest as pharmaceutical lead compounds. The purpose of our research was to define an efficent protocol for the assembly of the C-10 trifluoromethyl prostanoid mentioned in the title. This compound was predicted to show strong antitumor activity on the basis of the known structure-activity relationships within this series. A novel strategy for assembling the carbon skeleton of Delta(7)-unsaturated prostanoids bearing oxygen functionality at C-12 through an ionic electrocyclic process has been described. Key steps of the synthesis are the preparation of dieneone 14b through an electrocyclic ring-opening reaction and the ionic electrocyclization of 26a, which creates the functionalized carbon skeleton. The target compound was found to be cytotoxic in vitro against two human tumor cell lines in the low &mgr;M range, confirming our prediction.