Total Synthesis of Thiostrepton. Retrosynthetic Analysis and Construction of Key Building Blocks

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• 作者：K. C. Nicolaou ; Brian S. Safina ; Mark Zak ; Sang Hyup Lee ; Marta Nevalainen ; Marco Bella ; Anthony A. Estrada ; Christian Funke ; Fré ; dé ; ric J. Zé ; cri ; and Stephan Bulat
• 刊名：Journal of the American Chemical Society
• 出版年：2005
• 出版时间：August 10, 2005
• 年：2005
• 卷：127
• 期：31
• 页码：11159 - 11175
• 全文大小：783K
• 年卷期：v.127,no.31(August 10, 2005)
• ISSN：1520-5126

文摘

The first phase of the total synthesis of thiostrepton (1), a highly complex thiopeptide antibiotic,is described. After a brief introduction to the target molecule and its structural motifs, it is shown thatretrosynthetic analysis of thiostrepton reveals compounds 23, 24, 26, 28, and 29 as potential key buildingblocks for the projected total synthesis. Concise and stereoselective constructions of all these intermediatesare then described. The synthesis of the dehydropiperidine core 28 was based on a biosynthetically inspiredaza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plaguedwith several problems which were, however, resolved satisfactorily by systematic investigations. Thequinaldic acid fragment 24 and the thiazoline-thiazole segment 26 were synthesized by a series of reactionsthat included asymmetric and other stereoselective processes. The dehydroalanine tail precursor 23 andthe alanine equivalent 29 were also prepared from the appropriate amino acids. Finally, a method wasdeveloped for the direct coupling of the labile dehydropiperidine key building block 28 to the more advancedand stable peptide intermediate 27 through capture with the highly reactive alanine equivalent 67 underconditions that avoided the initially encountered destructive ring contraction process.