Stereoselective Synthesis of Isochromanones by an Asymmetric Ortho-Lithiation Strategy: Synthetic Access to the Isochromanone Core of the Ajudazols.

Abstract

Full details on the design, development, and application of a highly stereoselective strategy for the synthesis of isochromanones are reported. The method is based on an asymmetric ortho lithiation with aldehyde electrophiles and utilizes the chiral memory of a preoriented atropisomeric amide axis for stereocontrol. For direct transformation of sterically hindered amides to isochromanones, efficient and mild one-pot protocols involving either O-alkylation or acidic microwave activation were developed. The procedures may be applied also to highly functionalized as well as stereochemically complex and sensitive substrates and demonstrate a high protective group tolerance. Furthermore, asymmetric crotylborations of axially chiral amides were studied in detail. These methodologies enable a general access to all possible stereoisomers of hydroxyl-isochromanones with up to three contiguous stereocenters. The true applicability of our approach was finally demonstrated by synthesis of the authentic anti,anti-configured isochromanone core of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain from myxobacteria.