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

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• 作者：Prof. Dr. K. C. Nicolaou ; Dr. Kiran Kumar Pulukuri ; Ruocheng Yu ; Dr. Stephan Rigol ; Dr. Philipp Heretsch ; Dr. Charles I. Grove ; Christopher R. H. Hale and Dr. Abdelatif ElMarrouni
• 刊名：Chemistry - A European Journal
• 出版年：2016
• 出版时间：June 13, 2016
• 年：2016
• 卷：22
• 期：25
• 页码：8559-8570
• 全文大小：911K
• ISSN：1521-3765

文摘

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.