A vinylogous aldol‐type reaction of allylazaarenes and aldehydes is disclosed that affords a series of chiral γ‐hydroxyl‐α,β‐unsaturated azaarenes in moderate to excellent yields with high to excellent regio‐ and enantioselectivities. With (R,RP)‐TANIAPHOS and (R,R)‐QUINOXP* as the ligand, the carbon‐carbon double bond in the products is generated in (E)‐form. With (R)‐DTBM‐SEGPHOS as the ligand, (Z)‐form carbon‐carbon double bond is formed in the major product. In this vinylogous reaction, aromatic, α,β‐unsaturated, and aliphatic aldehydes are competent substrates. Moreover, a variety of azaarenes, such as pyrimidine, pyridine, pyrazine, quinoline, quinoxaline, quinazoline, and benzo[d]imidazole are well‐tolerated. At last, the chiral vinylogous product is demonstrated as a suitable Michael acceptor towards CuI‐catalyzed nucleophilic addition with organomagnesium reagents.

Asymmetric alkylation of enolates is one of the most direct and important reactions to prepare α-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 α-imino-esters with various alkyl halides, including allyl bromides, propargyl bromide, benzyl bromides, α-bromo carbonyl compounds, and alkyl iodides. Both linear and cyclic α-imino-esters serve as competent pronucleophiles in the alkylation, which affords α-amino acid derivatives bearing either a trisubstituted or a tetrasubstituted stereogenic carbon center in high to excellent enantioselectivity. Control experiments indicate that the α-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.

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.