C-selective and diastereoselective alkyl addition to ß,γ-alkynyl-α-imino esters with zinc(II)ate complexes.

Since umpolung α-imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α-amino acid derivatives. An unusual C-alkyl addition to α-imino esters using a Grignard reagent (RMgX)-derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX](+) moiety, a nucleophilic [R3 Zn](-) moiety, and 2 [MgX2 ]. Therefore, the ionically separated [R3 Zn](-) selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX](+) . In particular, chiral ß,γ-alkynyl-α-imino esters can strongly promote highly regio- and diastereoselective C-alkylation because of structural considerations, and the corresponding optically active α-quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.

Zinc(II)-catalyzed addition of Grignard reagents to ketones.

The addition of organometallic reagents to carbonyl compounds has become a versatile method for synthesizing tertiary and secondary alcohols via carbon-carbon bond formation. However, due to the lack of good nucleophilicity or the presence of strong basicity of organometallic reagents, the efficient synthesis of tertiary alcohols from ketones has been particularly difficult and, thus, limited. We recently developed highly efficient catalytic alkylation and arylation reactions to ketones with Grignard reagents (RMgX: R = alkyl, aryl; X = Cl, Br, I) using ZnCl(2), Me(3)SiCH(2)MgCl, and LiCl, which effectively minimize problematic side reactions. In principle, RMgBr and RMgI are less reactive than RMgCl for the addition to carbonyl compounds. Therefore, this novel method with homogeneous catalytic ZnCl(2) x Me(3)SiCH(2)MgCl x LiCl is quite attractive, since RMgBr and RMgI, which are easily prepared and/or commercially available, like RMgCl, can be applied successfully. As well as ketones and aldehydes, aldimines were effectively applied to this catalysis, and the corresponding secondary amines were obtained in high yield. With regard to mechanistic details concerning beta-silyl effect and salt effect, in situ-prepared [R(Me(3)SiCH(2))(2)Zn](-)[Li](+)[MgX(2)](m)[LiCl](n) (X = Cl/Br/I) is speculated to be a key catalytic reagent to promote the reaction effectively. The simplicity of this reliable ZnCl(2) x Me(3)SiCH(2)MgCl x LiCl system in the addition of Grignard reagents to carbonyl compounds might be attractive for industrial as well as academic applications.

Zinc(II)-catalyzed Grignard additions to ketones with RMgBr and RMgI.

Highly efficient alkylations and arylations of ketones with Grignard reagents (RMgBr and RMgI) have been developed using catalytic ZnCl(2), Me(3)SiCH(2)MgCl, and LiCl. Tertiary alcohols were obtained in high yields with high chemoselectivities, while minimizing undesired side products produced by reduction and enolization.