Total Synthesis of Δ12‐Prostaglandin J3: Evolution of Synthetic Strategies to a Streamlined Process

The total synthesis of Δ¹²‐prostaglandin J₃ (Δ¹²‐PGJ₃, 1 ), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross‐conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14 , whose lone stereocenters were generated by an asymmetric Tsuji–Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent‐governed regioselectivity pattern for the Rh‐catalyzed C?H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14 , exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57 , and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large‐scale production of Δ¹²‐PGJ₃ and designed analogues for further biological and pharmacological studies.