One‐Pot Oxidative Heterofunctionalization of Resorcinolic Cannabinoids to Non‐thiophilic Aminocannabinoquinones

Aminocannabinoquinones are an emerging class of next generation semi-synthetic cannabinoids exemplified by VCE-004.8 (1c), a compound currently in phase 2 development for scleroderma. Aminocannabinoquinones have been so far obtained from resorcinolic cannabinoids by a two-step protocol involving oxidation to a hydroxyquinone followed by tandem aza-Michael trapping by a primary amine and in situ reoxidation. To improve this synthesis and to broaden its substrate range, we have capitalized on the dual ability of manganese (III) acetate hydrate (MAH) to act as a one-electron oxidant for electron-rich aromatics as well as a Lewis acid promoter for Michael addition. This led to the development of a one-pot protocol for the oxidative heterofunctionalization of cannabinoids to aminocannabinoquinones suitable for the expeditious generation of libraries. Unlike cannabinoquinones, these amino derivatives are not thiophylic, providing a possible rationalization for the different stability and biological profile of the two classes of compounds.