Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

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• 作者：Pixu Li ; Cory D. Evans ; Yongzhong Wu ; Bin Cao ; Ernest Hamel ; Madeleine M. Joullié
• 刊名：Journal of the American Chemical Society
• 出版年：2008
• 出版时间：February 20, 2008
• 年：2008
• 卷：130
• 期：7
• 页码：2351 - 2364
• 全文大小：404K
• 年卷期：v.130,no.7(February 20, 2008)
• ISSN：1520-5126

文摘

Ustiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic corestructure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis ofustiloxin D was achieved in 31 linear steps using an S_NAr reaction. An NOE study of this synthetic productshowed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergentsyntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achievea better macrolactamization strategy. Ustiloxins D, F, and eight analogues (14-MeO-ustiloxin D, fouranalogues with different amino acid residues at the C-6 position, and three (9R,10S)-epi-ustiloxin analogues)were prepared via the second-generation route. Evaluation of these compounds as inhibitors of tubulinpolymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast,the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential forinhibition of tubulin polymerization.