Stream-lined synthesis of 3-hydroxy-β-lactams: Norrish-Yang type II photocyclizations of β-ketoformamides

• Published in: Tetrahedron 2018-05, Vol.74 (22), p.2743-2753
• Main Authors: Markley, Jana L., Morse, Tyler L., Rath, Nigam P., Wencewicz, Timothy A.
• Format: Article
• Language: English
• Subjects: 3-Hydroxy-β-lactams; Norrish-Yang cyclization; Photocyclization; Radical chemistry; β-Ketoformamide formation; β-Lactam synthesis
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2018.04.040

A photochemical approach to 3-phenyl-3-hydroxy-β-lactams (3-HβLs) is reported. Irradiation of aryl-β-ketoformamides with a UV light band centered at 300 nm provides the corresponding 3-aryl-3-HβLs with good conversion. The scope of the photocyclization is explored with an electronically diverse panel of substrates that provides mechanistic insight supporting a Norrish-Yang type II cyclization. A flexible synthetic route to phenyl-β-ketoformamides, followed by photoirradiation, allows for efficient incorporation of the β-lactam pharmacophore into aromatic organic scaffolds. Taken collectively, the improved and optimized synthetic route to provide both β-ketoformamides and 3-HβLs—in combination with the expanded analysis of substrate scope and limitations—reported herein will serve as a necessary reference for the direct, atom-economical, radical-mediated installation of 3-HβL scaffolds en route to the generation of other biologically active small molecules. [Display omitted]