On the Origin of Rh-Catalyzed Selective Ring-Opening Amidation of Substituted Cyclopropanols to Access β2‑Amino Ketones

• Published in: Journal of the American Chemical Society Vol. 144; no. 8; pp. 3667 - 3675
• Main Authors: Lee, Minhan, Heo, Joon, Kim, Dongwook, Chang, Sukbok
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.03.2022; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; BETA-AMINO KETONES; ASYMMETRIC-SYNTHESIS; ACID; HYDROGENATION; VINYL AZIDES; MANNICH-TYPE REACTIONS; IMINES; ENANTIOSELECTIVE CONJUGATE ADDITION; C-H AMIDATION; BOND
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c12934

β2-Amino carbonyls, an α-substituted β-amino scaffold, hold a prominent place in the development of new pharmaceuticals and peptidomimetics. Herein, we report a highly efficient Rh-catalyzed ring-opening amidation of substituted cyclopropanols, which turned out to serve as a linchpin for the selective synthesis of β2-amino ketones to outcompete the formation of β3-isomers. Instead of the generally accepted rationale to consider steric factors for the β2-selectivity, orbital interaction was elucidated to play a more critical role in the amidative ring-opening of cyclopropanols to generate the key Rh–C intermediate. Subsequent inner-sphere acylnitrene transfer was achieved in excellent efficiency (TON > 5000) by using readily accessible dioxazolones as the amino source to afford β2-amino ketones with broad applicability.