Asymmetric 1,4-Addition Reactions Catalyzed by N-Terminal Thiourea-Modified Helical l-Leu Peptide with Cyclic Amino Acids

N-terminal thiourea-modified l-Leu-based peptide {(3,5-diCF(3)Ph)NHC(=S)-(l-Leu-l-Leu-Ac(5)c)(2)-OMe} with five-membered ring alpha,alpha-disubstituted alpha-amino acids (Ac(5)c) catalyzed a highly enantioselective 1,4-addition reaction between beta-nitrostyrene and dimethyl malonate. The enantioselective reaction required only 0.5 mol % chiral peptide-catalyst in the presence of (Pr2EtN)-Pr-i (2.5 equiv.), and gave a 1,4-adduct with 93 % ee of an 85 % yield. As Michael acceptors, various beta-nitrostyrene derivatives such as methyl, p-fluoro, p-bromo, and p-methoxy substituents on the phenyl group, 2-furyl, 2-thiophenyl, and naphthyl beta-nitroethylenes could be applied. Furthermore, various alkyl malonates and cyclic beta-keto-esters could be used as Michael donors. It became clear that the length of the peptide chain, a right-handed helical structure, amide N-Hs, and the N-terminal thiourea moiety play crucial roles in asymmetric induction.

Automated summary

The N-terminal thiourea-modified l-Leu-based peptide catalyst demonstrated high enantioselectivity in the 1,4-addition reaction, requiring only a small amount for efficient reaction under different substrate and donor conditions.