Asymmetric Protonation of Enolates with Optically Active Imides as Proton Sources

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Asymmetric protonation of prochiral metal enolates is an effective route to optically active carbonyl compounds. Although a number of groups have made important contributions to the continuing progress in this process, most of these are the reactions of enolates having polar groups including amino, hydroxyl, or phenyl groups, and there have been few satisfactory reports on the asymmetric induction of enolates of simple ketones such as 2-methylcyclohexanone. We have already reported that the new chiral proton source, (S,S) -or (R,R) -imide, which possesses an asymmetric 2-oxazoline ring, can be easily prepared from Kemp's tricarboxylic acid and (1R,2S) -or (1S,2R) -2-amino-1,2-diphenylethanol, and protonates various lithium enolates of alpha-monoalkylatedcycloalkanones with excellent to moderate enantioselectivity.In this research, we further examined the asymmetric protonation of simple prochiral metal enolates with the chiral imide and related imides. An increase in enantioselectivity … More was observed in the asymmetric protonation of prochiral lithium enolates with (S,S) -imide using lithium salt as an additive. For example, (R) -enriched 2-n-pentylcyclopentanone was obtained in a nearly quantitative yield with 90% ee when the corresponding lithium enolate was generated in the presence of 5 equiv of LiBr in Et_2O and was protonated with (S,S) -imide in THF.Higher enantioselectivity was observed for the reaction of lithium enolate of 2-methylcyclohexanone with optically active 1-cyclohexylethylamine derived (S) -or (R) -imide, which possesses a chiral amide group, than with (S,S) - or (R,R) -imide. Noteworthy was the fact that the enantioselectivity was highly dependent on the steric bulkiness of alkyl substituents of cyclohexane ring of the imide. These chiral imides were further successfully applied to a diastereoselective protonation of a chiral enolate. When the lithium enolate of (-) -menthone was protonated by (S,S) -imide or (R) -imide, cis-ketone was the major product formed. In contrast, a high trans-selectivity was obtained for the reaction with (R,R) -imide or (S) -imide. The catalytic process of this diastereoselective protonation has been realized using a catalytic amount of these chiral imides and stoichiometric amount of an achiral proton source. Less