Catalysis‐Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester

Abstract

AbstractA concise and stereoselective total synthesis of the clinically relevant tricyclic prostaglandin D2 metabolite (tricyclic‐PGDM) methyl ester in racemic form was accomplished in eight steps from a readily available known cyclopentene‐diol derivative. The synthesis features a nickel‐catalyzed Ueno–Stork‐type dicarbofunctionalization to generate two consecutive stereocenters, a palladium‐catalyzed carbonylative spirolactonization to build the core oxaspirolactone, and a Z‐selective cross‐metathesis to introduce the (Z)‐3‐butenoate side chain, a group challenging to introduce through traditional Wittig protocols and troublesome for the two previous total syntheses. A general Z‐selective cross‐metathesis protocol to construct (Z)‐β,γ‐unsaturated esters was also developed that has broad functional group tolerance and high stereoselectivity. Additionally, our synthesis already accumulated 75 mg of valuable material for an 18O‐tricyclic‐PGDM‐based assay used in clinical settings for inflammation.