Copper(I)-catalyzed asymmetric alkylation of -imino-esters

Asymmetric alkylation of enolates is one of the most direct and important reactions to prepare & alpha;-chiral carbonyl compounds. Except for the classical methods that rely on the use of chiral auxiliaries, asymmetric catalysis emerged as a powerful tool, especially asymmetric phase-transfer catalysis. However, in the field of transition metal catalysis, only limited success with asymmetric alkylation of enolates was achieved. Hereby, we disclose a copper(I)-catalyzed asymmetric alkylation of & alpha;-imino-esters with various alkyl halides, including allyl bromides, propargyl bromide, benzyl bromides, & alpha;-bromo carbonyl compounds, and alkyl iodides. Both linear and cyclic & alpha;-imino-esters serve as competent pronucleophiles in the alkylation, which affords & alpha;-amino acid derivatives bearing either a trisubstituted or a tetrasubstituted stereogenic carbon center in high to excellent enantioselectivity. Control experiments indicate that the & alpha;-imino-ester is activated by a chiral copper(I)-phosphine complex through coordination, thus enabling facile deprotonation to provide a stabilized copper(I)-enolate in the presence of a mild base. Finally, the mildly basic nature allows the asymmetric alkylation of chiral dipeptides with excellent both chemo- and enantioselectivities. Asymmetric alkylation of enolates is an important method for the formation of & alpha;-stereogenic carbonyls but generally requires the introduction and then removal of chiral auxiliaries. Here, the authors report a copper-catalyzed asymmetric alkylation of & alpha;-amino esters.