Gram-Scale Enantioselective Formal Synthesis of Morphine through an ortho-para Oxidative Phenolic Coupling Strategy

A gram-scale catalytic enantioselective formal synthesis of morphine is described. The key steps of the synthesis involve an ortho-para oxidative phenolic coupling and a highly diastereoselective desymmetrization of the resulting cyclohexadienone that generates three of the four morphinan ring junction stereocenters in one step. The stereochemistry is controlled from a single carbinol center installed through catalytic enantioselective hydrogenation. These transformations enabled the preparation of large quantities of key intermediates and could support a practical and scalable synthesis of morphine and related derivatives.