Enantioselective Synthesis of α-Quaternary Isochromanes by Oxidative Aminocatalysis and Gold Catalysis

A novel strategy that combines oxidative aminocatalysis and gold catalysis allows the preparation of chiral alpha-quaternary isochromanes, a motif that is prevalent in natural products and synthetic bioactive compounds. In the first step, alpha-branched aldehydes and propargylic alcohols are transformed into alpha-quaternary ethers with excellent optical purities (>90 % ee) via oxidative umpolung with DDQ and an amino acid-derived primary amine catalyst. Subsequent gold(I)-catalyzed intramolecular hydroarylation affords the isochromane products with retention of the quaternary stereocenter. A second approach explores the use of allylic alcohols as reaction partners for the oxidative coupling to furnish alpha-quaternary ethers with generally lower enantiopurities. Stereoretentive cyclization to isochromane products is achieved via intramolecular Friedel-Crafts type alkylation with allylic acetates as a reactive handle. A number of synthetic elaborations and a biological study on these alpha-quaternary isochromanes highlight the potential applicability of the presented method.