Conformation-controlled catalytic asymmetric synthesis of Swaminathan ketones

Abstract

Besides numerous synthetic and biological applications, the catalytic construction of chiral Swaminathan ketones and their analogues possessing a bicyclo[5.4.0]undecane core structure has remained challenging for the scientific community for over four decades. Not more than five Swaminathan ketones (S. ketones) and their analogues are known in the literature to date. Herein, we report an unprecedented organocatalytic asymmetric desymmetrization strategy for the synthesis of chiral S. ketones and their analogues with excellent enantioselectivities from the corresponding 2-alkyl-2-(3-oxobutyl)-cycloheptane-1,3-diones via amine/acid-catalysed conformation-controlled intramolecular aldol condensation. We further reported a neat protocol for the high-yielding synthesis of functionally diverse synthons, 2-alkyl-2-(3-oxobutyl)-cycloheptane-1,3-diones from 2-alkylcycloheptane-1,3-diones via Michael addition. Finally, we also reported the powerful green organocatalytic reductive coupling protocol for generating a huge library of 2-alkylcycloheptane-1,3-diones from the conformationally flexible cycloheptane-1,3-dione and readily available aldehydes, which are potential synthons for the synthesis of bicyclo[5.4.0]undecane skeletons. Constructing a sustainable library of functionally rich chiral S. ketones with excellent enantioselectivities through conformation-controlled intramolecular aldol condensation via asymmetric desymmetrization and their interesting synthetic transformations with high selectivities are the key attractions of this study.