The Total Synthesis of the Annonaceous Acetogenin 10-Hydroxyasimicin

摘要

The annonaceous acetogenins comprise a class of almost 400 natural products that exhibit a remarkably broad spectrum of biological activity. They function as insecticides, fungicides, herbicides, and, perhaps most importantly, in vivo antitumor agents and have been shown to overcome resistance in multidrug-resistant tumors.[1] Structurally, the acetogenins are characterized by a long lipophilic tail, a central polyoxygenated core, and a terminal α,β-unsaturated γ-lactone. The structural diversity in this family arises principally from variations in the stereochemistry and connectivity of the polyoxygenated central core, which can consist of one or more tetrahydrofuranyl (THF) rings or, occasionally, a tetrahydropyranyl (THP) ring with various patterns of hydroxylation. These variations and the stereochemical consequences give rise to an impressive molecular diversity within the family. Owing to their biological activity and limited availability from natural sources, these compounds have attracted worldwide attention and have become the targets for total synthesis for a number of research groups,[2]-[9] including our own.[10] The majority of publications to date have focused on the synthesis of individual members of the family that suit a particular reaction type or stereochemical outcome. Motivated by the bioactivity of the annonaceous acetogenins, we embarked on a project to develop a more general route that utilizes an orthogonal and modular templating approach to provide access to many members in the series.