Step-Economical Synthesis Of Clinprost And Analogs Utilizing A Novel Decarboxylation Reaction

Abstract We present our step-economical synthesis of clinprost, the methyl ester of isocarbacyclin, and analogs. Isocarbacyclin is a valuable target due to its neuroprotection from the oxidative damage after a stroke. Specifically, we utilized a palladium-catalyzed decarboxylative coupling of a pentadienyl dienoate, a rhodium-catalyzed diene-diene [2+2+1] cycloaddition, and a ruthenium-catalyzed cross-metathesis reaction. The decarboxylation reaction is the first decarboxylation of its type since the carboxyl-bearing carbon does not possess an anion-stabilizing group. In this chapter, we present some of our research into this novel reaction. The diene-diene [2+2+1] cycloaddition is the first cyclocarbonylation between two dienes. The metathesis reaction is particularly valuable since it allows for late-stage diversification. These three metal-catalyzed reactions enabled us to complete the synthesis of clinprost in nine steps, seven for some analogs, instead of the 15 or more steps that have been previously reported.