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

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.