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

Abstract

AbstractA novel strategy that combines oxidative aminocatalysis and gold catalysis allows the preparation of chiral α‐quaternary isochromanes, a motif that is prevalent in natural products and synthetic bioactive compounds. In the first step, α‐branched aldehydes and propargylic alcohols are transformed into α‐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 α‐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 α‐quaternary isochromanes highlight the potential applicability of the presented method.