Asymmetric Synthesis of β‐Lactams through Copper‐Catalyzed Alkyne–Nitrone Coupling with a Prolinol–Phosphine Chiral Ligand

• Published in: Chemistry : a European journal 2017-06, Vol.23 (35), p.8400-8404
• Main Authors: Takayama, Yurie, Ishii, Takaoki, Ohmiya, Hirohisa, Iwai, Tomohiro, Schwarzer, Martin C., Mori, Seiji, Taniguchi, Tohru, Monde, Kenji, Sawamura, Masaya
• Format: Article
• Language: English
• Subjects: Alkynes - chemistry; asymmetric catalysis; beta-Lactams - chemical synthesis; Catalysis; cooperative catalysis; copper; Copper - chemistry; Drug Evaluation, Preclinical - methods; Humans; Hydrogen Bonding; Ligands; Nitrogen Oxides - chemistry; nitrones; Phosphines - chemistry; Pyrrolidines - chemistry; Stereoisomerism; Structure-Activity Relationship; β-lactam
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201702070

Prolinol–phosphine chiral ligands enabled highly enantioselective copper‐catalyzed intermolecular alkyne–nitrone coupling (Kinugasa reaction) to produce 1,3,4‐trisubstituted chiral β‐lactams. A high level of enantiocontrol was achieved not only with aryl‐ or alkenylacetylenes but also with alkylacetylenes, which were important but unfavorable substrates in the previously reported protocols. Two‐point hydrogen bonding between the chiral ligand and the nitrone oxyanion consisting of O−H⋅⋅⋅O and C(sp3)−H⋅⋅⋅O hydrogen bonds is proposed. β‐Lactam synthesis: Prolinol–phosphine chiral ligands enabled highly enantioselective copper‐catalyzed intermolecular alkyne–nitrone coupling (Kinugasa reaction) to produce 1,3,4‐trisubstituted chiral β‐lactams. Two‐point hydrogen bonding between the chiral ligand and the nitrone oxyanion consisting of O−H⋅⋅⋅O and C(sp3)−H⋅⋅⋅O hydrogen bonds is proposed.