Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

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• 作者：Ian Paterson  ; ;   ; ^{ip100@cam.ac.uk} ; Victoria A. Steadman neé ; Doughty ; Malcolm D. McLeod ; Thomas Trieselmann
• 关键词：Macrolide ; Aldol reaction ; Enzyme inhibitor ; Stille coupling ; Macrolactonisation ; Protecting groups
• 刊名：Tetrahedron
• 出版年：2011
• 出版时间：30 December 2011
• 年：2011
• 卷：67
• 期：52
• 页码：10119-10128
• 全文大小：1280 K

文摘

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8 % yield over 26 steps. The three key fragments, C1¨CC13 vinyl iodide, C14¨CC22 vinyl stannane and C23¨CC28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1¨CC13 vinyl iodide and C14¨CC22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1¨CC13 and C14¨CC22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13¨CC28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting ¦Â-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.