Single- and double-chained truncated jaspine B analogues: asymmetric synthesis, biological evaluation and theoretical study of an unexpected 5-endo-dig process

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作者：

Y Salma，S Ballereau，S Ladeira，C Lepetit，R Chauvin，N Andrieu-Abadie，Y Génisson

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摘要：

An optimized synthesis of jaspine B analogues bearing an -octyl or a -fluorophenethyl lipophilic appendage was developed. Key to the approach was the use of acetylenic nucleophiles for the stereocontrolled introduction of the side chain and the implementation of a novel cyclization procedure to build the tetrahydrofuran ring. Three -substituted amine or amide derivatives were also accessed. The biological activity of these four jaspine B analogues was shown to strongly depend on the nature of both the -substituent and the aliphatic moiety connected to the tetrahydrofuran ring. Gratifyingly, the truncated jaspine B derivative proved to be a pro-apoptotic inhibitor of the conversion of ceramide into sphingomyelin. Finally, the efficient formation of a fused bis-furan derivative according to a 5-- process was observed under saponification conditions. On the basis of a theoretical study, a mechanistic pathway was delineated highlighting the Lewis acidity of the K ion as the driving force for this transformation in a strongly alkaline medium.Graphical abstract

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关键词：

Sphingomyelin synthase Apoptosis 5-- Furan

DOI：

10.1016/j.tet.2011.04.027

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年份：

2011