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

• Published in: Chemistry : a European journal Vol. 22; no. 25; pp. 8559 - 8570
• Main Authors: Nicolaou, K. C., Pulukuri, Kiran Kumar, Yu, Ruocheng, Rigol, Stephan, Heretsch, Philipp, Grove, Charles I., Hale, Christopher R. H., ElMarrouni, Abdelatif
• Format: Journal Article
• Language: English
• Published: Blackwell Publishing Ltd 13.06.2016
• Subjects: antitumor agent; asymmetric catalysis; chiral auxiliary; prostaglandin; total synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201601449

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. Streamlining the synthesis of Δ12‐prostaglandin J3 proceeded through improvements in the construction of both the key enone and aldehyde building blocks, exploration of the chemistry of the hitherto underutilized chiral lactone synthon, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large‐scale production of Δ12‐prostaglandin J3 and designed analogues for further biological and pharmacological studies.