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

Organic and Biomolecular Chemistry. 2023. Vol. 21. No. 46. P. 9143–9149.

Arsenov M., Stoletova N., Smol'yakov A., Savel'yeva T., Maleev V., Loginov D. A., Larionov V.

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.

Keywords: asymmetric synthesis, amino acids, rhodium complexes, C-H activation, Homogeneous catalysis