（−）-L-755,807の全合成およびアミロイドβ凝集阻害活性

抄録

(−)-L-755,807, which was isolated from an endophytic fungus, Microsphaeropsis sp., consists of a characteristic epoxy-γ-lactam ring and a tetraene-containing side chain, and exhibits bradykinin B2 receptor antagonist activity. The first total synthesis of (−)-L-755,807 was accomplished through a convergent approach, employing a late-stage coupling between the ring and side-chain segments. The ring segment was efficiently synthesized by a novel syn-selective Darzens reaction between di-tert-butyl bromomalonate and α-alkoxy aldehyde, and the side-chain segment was prepared by a highly stereoselective Horner-Wadsworth-Emmons reaction as a key step to construct the tetraene part. This synthesis enabled us to assign the relative and absolute configurations of (−)-L-755,807. Furthermore, we discovered an additional biological activity of this compound, namely, potent amyloid β aggregation inhibitory activity, which could be useful in the treatment of Alzheimer’s disease. The epoxy-γ-lactam moiety was identified as a likely pharmacophore for this activity. In this article, we describe the total synthesis, stereochemical assignment, and biological evaluation of (−)-L-755,807.