Enantioselective Copper-Catalyzed Conjugate Addition of Trimethylaluminum to β,γ-Unsaturated α-Ketoamides: Efficient Access to γ-Methyl-Substituted Carbonyl Compounds

摘要

Chiral α-,β-, or γ-methyl-substituted carbonyl groups are important scaffolds in organic synthesis and are present in numerous natural products. α-Methyl-substituted carbonyls can be easily obtained by asymmetric α-alkylation of carbonyls (Figure 1). One simple strategy to access β-methyl-substituted carbonyls is a copper-catalyzed asymmetric con- jugate addition (ACA) to α,β-unsaturated carbonyls, a reaction widely reported in the literature. But the preparation of chiral γ-methyl-substituted carbonyls is not so trivial compared to its parent α- and β-substituted carbonyls. The main methodology relies on ring-opening, by copper, of chiral cyclopropanes with subsequent decarboxylation and amide reduction (Figure 1, route a). By using this approach, Charette et al. reported one example of the preparation of γ-methyl-substituted aldehydes with complete retention of enantioselectivity.