Highly enantio- and diastereoselective organocatalytic desymmetrization of prochiral cyclohexanones by simple direct aldol reaction catalyzed by proline

A straightforward, efficient and highly enantio- and diastereoselective desymmetrization of 4-substituted cyclohexanones using proline as catalyst was investigated. Once a suitable catalyst system was obtained for the desymmetrization of 4-methylcyclohexanone (1a) by aldol addition, the reaction of different 4-substituted cyclohexanones with 4-nitrobenzaldehyde was studied. The final aldol adduct in excellent enantioselectivities and in good to excellent yields and diastereoselectivities was obtained. Both the UV and fluorescence spectra of the additive 4 f with different amounts of proline was used to investigate the stoichiometry between additives and proline in CHCl₃. The UV spectrum of compound 4 f showed a slight blue-shift to 360 nm, an absorbance increase at 360 nm and an isosbestic point around 310 nm with increasing concentration of proline. It was demonstrated that the use of simple hydrogen-bond donors as additives increases dramatically the efficiency of the process.