Total Synthesis of Δ(12) -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: Germany 13.06.2016
• Subjects: Aldehydes; Alkenes - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Catalysis; Cyclopentanes - chemistry; Prostaglandins - chemical synthesis; Prostaglandins - chemistry; Rhodium - chemistry; Stereoisomerism; antitumor agent; asymmetric catalysis; total synthesis; prostaglandin; chiral auxiliary
• ISSN: 1521-3765
• DOI: 10.1002/chem.201601449

The total synthesis of Δ(12) -prostaglandin J3 (Δ(12) -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 Δ(12) -PGJ3 and designed analogues for further biological and pharmacological studies.