The biological significance of sp3-rich synthetic scaffolds with natural product-like features yet distinct global frameworks is being increasingly recognised in medicinal chemistry and biochemistry. Taking inspiration from the vast array of bioactive, bridged alkaloids, we report the synthesis of unique, densely functionalised tricyclic scaffolds based on nitrogen-bridged, octahydrobenzofurans and octahydroindoles. These heterocycle-rich frameworks were assembled by a one-pot, two-step bridge-forming reductive amination process, which was shown to proceed via caged, heteroadamantane intermediates that thermodynamically drive an exo–endo epimerisation, enabling intramolecular azaMichael addition over the concave face of the fused bicyclic precursors. In addition to evaluating the scope of this aza bridge-forming reaction, further stereochemical complexity was introduced by subsequent diastereoselective ketone reductions and other manipulations. Finally, strategic diversity points (amino, carboxy) were decorated with common medicinal chemistry fragments, providing a set of exemplar derivatives with Lipinski compliant physicochemical properties.

中文翻译：

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氮桥连、天然产物类八氢苯并呋喃和八氢吲哚：通过笼式杂金刚烷进行桥连还原胺化的范围和机制

富含 sp3 的合成支架具有类似天然产物的特征但具有独特的全局框架的生物学意义在药物化学和生物化学中越来越得到认可。从大量具有生物活性的桥连生物碱中汲取灵感，我们报告了基于氮桥连、八氢苯并呋喃和八氢吲哚的独特、密集功能化的三环支架的合成。这些富含杂环的框架是通过一锅两步桥形成还原胺化过程组装的，该过程显示通过笼状杂金刚烷中间体进行，这些中间体在热力学上驱动外-内差向异构化，使分子内 azaMichael 添加到凹面上稠合双环前体。除了评估这种氮杂桥形成反应的范围外，随后的非对映选择性酮还原和其他操作引入了进一步的立体化学复杂性。最后，战略多样性点（氨基、羧基）用常见的药物化学片段装饰，提供了一组具有 Lipinski 兼容物理化学特性的示例性衍生物。