Copper(I)-Catalyzed Asymmetric Synthesis of Unnatural α‑Amino Acid Derivatives and Related Peptides Containing γ‑(aza)Aryls

Chiral α-amino acids are indispensable compounds in organic chemistry, biochemistry, and medicinal chemistry. Herein, by means of copper­(I)-catalyzed asymmetric conjugate addition of derivatives of glycine, serine, cysteine, and β-amino-alanine to electron-deficient vinyl­(aza)­arenes, an array of novel unnatural chiral α-amino acid derivatives bearing a γ-(aza)­aryl is prepared in moderate to high yields with high enantioselectivity. Various azaarenes, such as pyrimidine, 1,3,5-triazine, pyridine, pyridine-N-oxide, quinoline, quinoxaline, purine, benzo­[d]­imidazole, benzothiazole, and 1,2,4-oxadiazole, are well tolerated. Moreover, the electrophiles are nicely extended to (Z)/(E) mixtures of electron-deficient butadienylpyridine and benzene, which are transformed to the corresponding chiral α-amino acid derivatives in high (E)/(Z) ratio and high enantioselectivity. More importantly, the present methodology is successfully applied in the catalytic asymmetric functionalization of Schiff bases derived from peptides, which finally afforded a new chiral tripeptide bearing two electron-deficient azaaryls and one electron-deficient aryl in high total yield with high diastereo- and excellent enantioselectivities.