Bifunctional squaramide catalysts with the same absolute chirality for the diastereodivergent access to densely functionalised cyclohexanes through enantioselective domino reactions. Synthesis and mechanistic studies

Abstract

We have developed a procedure for the stereoselective and diastereodivergent synthesis of densely functionalised cyclohexanes containing four stereocentres through an asymmetric Michael-initiated ring closure (MIRC) cascade reaction employing hydrogen-bond catalysis, which is able to prepare adducts with different absolute configurations starting from the same starting materials. The overall process involves a highly diastereo- and enantioselective Michael/ Henry cascade reaction between a wide range of nitroalkenes and a-nitro-d-oxo esters, allowing access to different diastereoisomers of the final adduct by introducing subtle changes in the general (R,R)-configured bifunctional tertiary amine/squaramide catalyst structure. Moreover, this methodology is also amenable to a three-component one-pot procedure, leading to the formation of the same adducts with very good results directly from commercially available reagents, on a multigram scale, and employing a very low catalyst loading. Furthermore, a detailed experimental and computational study is described which shows the origin of the diastereodivergent behaviour of these structurally similar catalysts and the nature of the substrate-catalyst interaction.