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

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journal contribution
posted on 02.10.2015, 00:00 by Manas K. Ghorai, Sandipan Halder, Subhomoy Das
A simple strategy for the synthesis of highly functionalized cyclohexanone derivatives containing an 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. An asymmetric version of the protocol was explored with (L)-menthol derived nonracemic substrates, and the corresponding nonracemic cyclohexanone derivatives containing an all-carbon quaternary center were obtained with excellent stereoselectivity (de, ee > 99%).