Direct Lactamization of β-Arylated δ-Aminopentanoic Acid Carboxamides: En Route to 4-aryl-2-Piperidones, Piperidines, Antituberculosis Molecule Q203 (Telacebec) and its Analogues

Abstract

We report the synthesis of 4-aryl-2-piperidone, 4-arylpiperidine motifs, antituberculosis molecule Q203 (Telacebec) and its analogues. Direct lactamization of β-C−H arylated N-phthaloyl δ-aminopentanoic acid carboxamides yielded 4-aryl-2-piperidone (4-aryl-δ-valerolactam) scaffolds. The required β-C−H arylated N-phthaloyl δ-aminopentanoic acid carboxamides were assembled via the Pd(II)-catalyzed, 8-aminoquinoline-aided, sp3 β-C−H activation and arylation method. The β-C−H arylated N-phthaloyl δ-aminopentanoic acid carboxamides containing both 8-aminoquinoline and N-phthaloyl protecting groups directly underwent the hydrazine-mediated lactamization to afford 4-aryl-2-piperidones. 4-Aryl-2-piperidone scaffolds were then converted into N-functionalized 4-aryl-2-piperidones, 4-arylpiperidines, which are structurally closer to bio-active 4-aryl- 2-piperidone and piperidine motifs. A synthetic route for assembling antituberculosis molecule Q203 and its analogues from the corresponding 4-aryl-2-piperidones was also shown.