A synthetic route to artificial chiral α-amino acids featuring a 3,4-dihydroisoquinolone core through a Rh(III)-catalyzed functionalization of allyl groups in chiral Ni(II) complexes.

Currently, non-proteinogenic α-amino acids (α-AAs) have attracted increasing interest in bio- and medicinal chemistry. In this context, the first protocol for the asymmetric synthesis of artificial α-AAs featuring a 3,4-dihydroisoquinolone core with two stereogenic centers was successfully elaborated. A straightforward Rh(III)-catalysed C-H activation/annulation reaction of various aryl hydroxamates with a set of robust and readily available chiral Ni(II) complexes, which have allylic appendages derived from glycine (Gly), alanine (Ala) and phenylalanine (Phe), allowed incorporation of a 3,4-dihydroisoquinolone scaffold into the chiral amino acid residue. The reaction was performed in methanol and under mild conditions (at room temperature under air atmosphere), providing separable diastereomeric complexes with up to 94% total yield. The target α-AA with a 3,4-dihydroisoquinolone core in an enantiopure form was subsequently released from the obtained chiral Ni(II) complexes via an acidic decomposition in aqueous HCl, along with the recovery of the chiral auxiliary ligand.

Correction: An asymmetric metal-templated route to amino acids with an isoquinolone core via a Rh(III)-catalyzed coupling of aryl hydroxamates with chiral propargylglycine Ni(II) complexes.

Correction for 'An asymmetric metal-templated route to amino acids with an isoquinolone core via a Rh(III)-catalyzed coupling of aryl hydroxamates with chiral propargylglycine Ni(II) complexes' by Mikhail A. Arsenov et al., Org. Biomol. Chem., 2022, 20, 9385-9391, https://doi.org/10.1039/D2OB01970A.

An asymmetric metal-templated route to amino acids with an isoquinolone core via a Rh(III)-catalyzed coupling of aryl hydroxamates with chiral propargylglycine Ni(II) complexes.

A general protocol for the asymmetric synthesis of artificial amino acids (AAs) comprising an isoquinolone skeleton was successfully elaborated via a straightforward Rh(III)-catalyzed C-H activation/annulation of various aryl hydroxamates with a series of robust chiral propargylglycine Ni(II) complexes derived from glycine (Gly), alanine (Ala) and phenylalanine (Phe) in a green solvent (methanol) under mild conditions (at room temperature under air). Notably, in the case of phenylalanine-derived complexes, the formation of unfavorable 4-substituted isoquinolone regioisomers was achieved by a catalyst control for the first time. The subsequent acidic decomposition of the obtained Ni(II) complexes provides the target unnatural α- and α,α-disubstituted AAs with an isoquinolone core in an enantiopure form.

Henry Reaction Revisited. Crucial Role of Water in an Asymmetric Henry Reaction Catalyzed by Chiral NNO-Type Copper(II) Complexes.

Chiral copper(II) and cobalt(III) complexes (1-5 and 6, respectively) derived from Schiff bases of (S)-2-(aminomethyl)pyrrolidine and salicylaldehyde derivatives were employed in a mechanistic study of the Henry reaction-type condensation of nitromethane and o-nitrobenzaldehyde in CH2Cl2 (CD2Cl2), containing different amounts of water. The reaction kinetics was monitored by 1H and 13C NMR. The addition of water had a different influence on the activity of the two types of complexes, ranging from a crucial positive effect in the case of the copper(II) complex 2 to insignificant in the case of the stereochemically inert cobalt(III) complex 6. No experimental support was found by 1H NMR studies for the classical Lewis acid complexation of the carbonyl group of the aldehyde by the central copper(II) ion, and, moreover, density functional theory (DFT) calculations support the absence of such coordination. On the other hand, a very significant complexation was found for water, and it was supported by DFT calculations. In fact, we suggest that it is the Brønsted acidity of the water molecule coordinated to the metal ion that triggers the aldehyde activation. The rate-limiting step of the reaction was the removal of an α-proton from the nitromethane molecule, as supported by the observed kinetic isotope effect equaling 6.3 in the case of the copper complex 2. It was found by high-resolution mass spectrometry with electrospray ionization that the copper(II) complex 2 existed in CH2Cl2 in a dimeric form. The reaction had a second-order dependence on the catalyst concentration, which implicated two dimeric forms of the copper(II) complex 2 in the rate-limiting step. Furthermore, DFT calculations help to generate a plausible structure of the stereodetermining transition step of the condensation.