Asymmetric radical cyclopropanation of dehydroaminocarboxylates: Stereoselective synthesis of cyclopropyl a-amino acids

A catalytic radical process has been developed for asymmetric cyclopropanation of dehydroaminocarboxylates with in situ-generated a-aryldiazomethanes via Co(II)-based metalloradical catalysis (MRC). Through fine-tuning the environments of D-2-symmetric chiral amido-porphyrin platform as the supporting ligands, the Co(II)-metalloradical system can effectively activate various alpha-aryldiazomethanes to cyclo-propanate different dehydroaminocarboxylates undermild conditions, enabling the stereoselective synthesis of chiral cyclopropyl alpha-amino acid derivatives. In addition to high yields and excellent enantioselectivities, the Co(II)-catalyzed asymmetric radical cyclopropanation exhibits (Z)-diastereoselectivity, which is the opposite of uncatalyzed thermal reaction. Combined computational and experimental studies support a stepwise radicalmechanism for the Co(II)-catalyzed cyclopropanation reaction. The resulting enantioenriched (Z)-alpha-amino-beta-arylcyclopropanecarboxylates, as showcased for the efficient synthesis of dipeptides, may serve as unique non-proteinogenic amino acid building blocks for the design and preparation of novel peptides with restricted conformations.

Automated summary

A catalytic radical process for asymmetric cyclopropanation using Co(II)-based metalloradical catalysis has been developed, enabling the stereoselective synthesis of chiral cyclopropyl alpha-amino acid derivatives with high yields, excellent enantioselectivities, and (Z)-diastereoselectivity. Computational and experimental studies support a stepwise radical mechanism for the reaction, showcasing potential applications in the synthesis of dipeptides.