Domino Michael–Michael and Aldol–Aldol Reactions: Diastereoselective Synthesis of Functionalized Cyclohexanone Derivatives Containing Quaternary Carbon Center

Abstract

A simple strategy for the synthesis of highly functionalized cyclohexanone derivatives containing all-carbon quaternary center from α-(aryl/alkyl)methylidene-β-keto esters or β-diketones via a K- enolate mediated domino Michael-Michael reaction sequence with moderate to good yield and excellent diastereoselectivity (de >99%) is described. Interestingly, Li-base mediated reaction of α-arylmethylidene-β-diketones affords functionalized 3,5-dihydroxy cyclohexane derivatives as the kinetically controlled products via a domino aldol-aldol reaction sequence with excellent diastereoselectivity. Li-enolates of the β-keto esters or β-diketones undergo facile domino Michael-Michael reaction with nitro-olefins to afford the corresponding nitrocyclohexane derivatives in good yields and excellent diastereoselectivity (de >99%). The formation of the products and the observed stereoselectivity were explained by plausible mechanisms and supported by extensive computational study. Asymmetric version of the protocol was explored with (L)-menthol derived non-racemic substrates and the corresponding non-racemic cyclohexanone derivatives containing all-carbon quaternary center were obtained with excellent stereoselectivity (de, ee >99%).