Modular Synthesis of Cyclopropane-Fused N-Heterocycles Enabled by Underexplored Diazo Reagents.
Modular Synthesis of Cyclopropane-Fused N-Heterocycles Enabled by Underexplored Diazo Reagents.
复制标题
DOI：
10.1002/anie.202203221
复制
发表时间：
2022-09-19
影响因子：
16.6
通讯作者：
Schreiber, Stuart L.
中科院分区：
文献类型：
--
作者：
Richter, Matthieu J. R.;Zecri, Frederic J.;Briner, Karin;Schreiber, Stuart L.
环丙烷稠合的N-杂环化合物在许多具有生物活性的化合物中具有重要作用，在药物化学中也是一种很有吸引力的骨架化合物。然而，获得结构和功能多样的环丙烷稠合的N杂环的合成路线仍然未被探索。利用新型的α-重氮酰化剂，我们报道了一种由不饱和胺直接和模块化合成环丙烷稠合内酰胺的通用方法。通过连续酰化、（3+2）环加成和断裂进行的操作简单的转化耐受广泛的官能团，并产生广泛的复杂分子支架，包括稠合、桥接和螺环系统。我们证明了这种转换的实用性，在简洁的治疗药物米那普仑和阿米替定的合成。实现了由容易获得的胺模块化合成环丙烷稠合的N-杂环。所公开的策略的关键是反应性α-重氮酰化剂的开发和实施，提供了获得结构和功能多样的产物的途径。该方法的应用展示在治疗药物米那普仑和阿米替定的简明合成。
Cyclopropane-fused N-heterocycles are featured in various biologically active compounds and represent attractive scaffolds in medicinal chemistry. However, synthesis routes to access structurally and functionally diverse cyclopropane-fused N heterocycles remain underexplored. Leveraging novel α-diazo acylating agents, we report a general approach for the direct and modular synthesis of cyclopropane-fused lactams from unsaturated amines. The operationally simple transformation, which proceeds through successive acylation, (3+2) cycloaddition and fragmentation, tolerates a broad range of functional groups and yields a wide spectrum of complex molecular scaffolds, including fused, bridged and spiro ring systems. We demonstrate the utility of this transformation in the concise syntheses of therapeutic agents milnaciprane and amitifadine. Modular synthesis of cyclopropane-fused N-heterocycles from readily available amines was achieved. Key to the disclosed strategy was the development and implementation of reactive α-diazo acylating agents, providing access to structurally and functionally diverse products. Application of the method is showcased in the concise syntheses of therapeutic agents milnaciprane and amitifadine.
登录
查看更多内容
影响因子：
4
作者：
Mix, Kalie A.;Aronoff, Matthew R.;Raines, Ronald T.
通讯作者：
Raines, Ronald T.
影响因子：
5.2
作者：
Jun JV;Raines RT
通讯作者：
Raines RT
影响因子：
1.8
作者：
DAUBEN, WG;HENDRICKS, RT;NG, HP
通讯作者：
NG, HP
影响因子：
3.6
作者：
Doyle, MP;Kalinin, AV
通讯作者：
Kalinin, AV
影响因子：
1.1
作者：
MOORE, R;MISHRA, A;CRAWFORD, RJ
通讯作者：
CRAWFORD, RJ