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<p>The direct incorporation of a single nitrogen atom into ketones or aldehydes represents one of the most valuable transformations for constructing amides and lactams, motifs that are ubiquitous in pharmaceutical manufacturing and industrial synthesis. Despite its importance, achieving precise stereochemical control in this process remains a formidable and long-standing challenge, primarily owing to the demanding reaction conditions typically required for such transformations. Here we show a highly enantioselective approach catalysed by a chiral phosphoric acid for the synthesis of enantioenriched five-membered to seven-membered lactams. This method uses prochiral cyclic ketones and readily available <i>O</i>-(sulfonyl)hydroxylamine reagents, proceeding via a Beckmann rearrangement with remarkable efficiency and stereocontrol. Our mechanistic investigations and theoretical calculations reveal that the sulfonyl-based leaving group plays a pivotal role in facilitating the rearrangement under mild conditions. This practical and robust protocol provides effective avenues for the efficient construction of chiral drug molecules, as demonstrated by the concise synthesis of the hydrochlorides of (<i>R</i>)-phenibut, (<i>S</i>)-pregabalin, (<i>R</i>)-baclofen, (<i>R</i>)-4-fluorophenibut, (<i>R</i>)-tolibut and (<i>R</i>)-phenotropil.</p><p></p>

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Asymmetric synthesis of enantioenriched lactams from cyclic ketones via Beckmann rearrangement

  • 期刊论文

  • 发表日期：

    2026年2月13日

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  • Sishi Zhong,
  • Lei Xu,
  • Mengru Guo,
  • Danyang Xie,
  • Yu Lan,
  • Yong Xia

摘要

The direct incorporation of a single nitrogen atom into ketones or aldehydes represents one of the most valuable transformations for constructing amides and lactams, motifs that are ubiquitous in pharmaceutical manufacturing and industrial synthesis. Despite its importance, achieving precise stereochemical control in this process remains a formidable and long-standing challenge, primarily owing to the demanding reaction conditions typically required for such transformations. Here we show a highly enantioselective approach catalysed by a chiral phosphoric acid for the synthesis of enantioenriched five-membered to seven-membered lactams. This method uses prochiral cyclic ketones and readily available O-(sulfonyl)hydroxylamine reagents, proceeding via a Beckmann rearrangement with remarkable efficiency and stereocontrol. Our mechanistic investigations and theoretical calculations reveal that the sulfonyl-based leaving group plays a pivotal role in facilitating the rearrangement under mild conditions. This practical and robust protocol provides effective avenues for the efficient construction of chiral drug molecules, as demonstrated by the concise synthesis of the hydrochlorides of (R)-phenibut, (S)-pregabalin, (R)-baclofen, (R)-4-fluorophenibut, (R)-tolibut and (R)-phenotropil.