Organocatalytic Sequential One-Pot Double Cascade Asymmetric Synthesis of Wieland−Miescher Ketone Analogues from a Knoevenagel/Hydrogenation/Robinson Annulation Sequence: Scope and Applications of Organocatalytic Biomimetic Reductions

A practical and novel organocatalytic chemo- and enantioselective process for the cascade synthesis of highly substituted 2-alkyl-cyclohexane-1,3-diones and Wieland−Miescher (W−M) ketone analogs is presented via reductive alkylation as a key step. First time, we developed the one-step alkylation of dimedone and 1,3-cyclohexanedione with aldehydes and Hantzsch ester through an organocatalytic reductive alkylation strategy. Direct combination of l-proline-catalyzed cascade Knoevenagel/hydrogenation and cascade Robinson annulation of CH acids (dimedone and 1,3-cyclohexanedione), aldehydes, Hantzsch ester, and methyl vinyl ketone furnished the highly functionalized W−M ketone analogues in good to high yields and with excellent enantioselectivities. Many of the reductive alkylation products show a direct application in pharmaceutical chemistry.