Stereocontrolled access to δ-lactone-fused-γ-lactams bearing angular benzylic quaternary stereocenters
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C-fused γ-lactam-lactones are resident in several bioactive molecules, including anticancer agents such as omuralide. In this embodiment, we report mild conditions for the catalytic halolactonization of lactam-tethered 5-aryl-4(E)-pentenoic acids. The use of dichloromethane as the solvent and Ph3PS as the catalyst led to predominant 6-endo-trig cyclization and furnished the trans-fused-γ-lactam-δ-lactones. The transformation is modular, regioselective, chemoselective, and diastereoselective. The γ-lactam-δ-lactones bear angular quaternary benzylic stereocenters, which is noteworthy since the presence of a quaternary carbon in bioactive small molecules often promotes an element of conformational restriction that imparts potency, selectivity, and metabolic stability. The generated halogen and lactone motifs are important functional handles for late-stage diversification.
Beng, T. K., Rodriguez, M. J., & Borg, C. (2022). Stereocontrolled access to δ-lactone-fused-γ-lactams bearing angular benzylic quaternary stereocenters. RSC Advances, 12(27), 17617–17620. https://doi.org/10.1039/d2ra02167f
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