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<p>Accessing <i>trans</i>-fused <i>N</i>-fused tricyclic frameworks with multiple contiguous stereocenters remains a major challenge in synthesis. We report a synergistic isothiourea/Ir-catalyzed [3 + 2] annulation of arylacetic acid esters with azabenzonorbornadienes, providing <i>trans</i>-fused tricyclic γ-lactams with three contiguous tertiary stereocenters in high regio-, enantio-, and diastereoselectivity. The method tolerates diverse arylacetates, heterocycles, and pharmaceutically relevant carboxylates, and is amenable to gram-scale synthesis. Mechanistic studies support a cooperative cycle involving C1-ammonium enolate formation and enantioselective S<sub>N</sub>2’ attack on the Ir-activated azabenzonorbornadiene. Downstream functionalizations, including epoxidation, hydrogenation, and amino alcohol formation, demonstrate the versatility of the products. This work establishes a concise and efficient platform for constructing sterically challenging <i>trans</i>-fused tricyclic γ-lactams, highlighting the potential of synergistic catalysis for complex stereocontrolled transformations.</p>

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Concise synthesis of chiral tricyclic γ-lactams via synergistic isothiourea/Ir catalyzed asymmetric [3 + 2] annulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月7日

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  • Guorong Xiao,
  • Mengjiao Yang,
  • Duanyang Kong

摘要

Accessing trans-fused N-fused tricyclic frameworks with multiple contiguous stereocenters remains a major challenge in synthesis. We report a synergistic isothiourea/Ir-catalyzed [3 + 2] annulation of arylacetic acid esters with azabenzonorbornadienes, providing trans-fused tricyclic γ-lactams with three contiguous tertiary stereocenters in high regio-, enantio-, and diastereoselectivity. The method tolerates diverse arylacetates, heterocycles, and pharmaceutically relevant carboxylates, and is amenable to gram-scale synthesis. Mechanistic studies support a cooperative cycle involving C1-ammonium enolate formation and enantioselective SN2’ attack on the Ir-activated azabenzonorbornadiene. Downstream functionalizations, including epoxidation, hydrogenation, and amino alcohol formation, demonstrate the versatility of the products. This work establishes a concise and efficient platform for constructing sterically challenging trans-fused tricyclic γ-lactams, highlighting the potential of synergistic catalysis for complex stereocontrolled transformations.