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

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%).