Direct amino acid-catalyzed cascade biomimetic reductive alkylations: application to the asymmetric synthesis of Hajos–Parrish ketone analogues

Abstract

A direct amino acid-catalyzed chemo- and enantioselective process for the double cascade synthesis of highly substituted 2-alkyl-cyclopentane-1,3-diones, 2-alkyl-3-methoxy-cyclopent-2-enones and Hajos–Parrish (H–P) ketone analogs is presented via reductive alkylation chemistry. For the first time, we have developed a single-step alkylation of cyclopentane-1,3-dione with aldehydes/ketones and a Hantzsch ester through an organocatalytic reductive alkylation strategy. A direct combination of amino acid-catalyzed cascade olefination–hydrogenation and cascade Robinson annulations of cyclopentane-1,3-dione, aldehydes/ketones, a Hantzsch ester and methyl vinyl ketone furnished the highly functionalized H–P ketone analogues in good to high yields and with excellent enantioselectivities. Many of the reductive alkylation products have shown direct applications in pharmaceutical chemistry.