Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes
Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes
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DOI：
10.1016/j.chempr.2018.10.017
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发表时间：
2019-01-10
期刊：
影响因子：
23.5
通讯作者：
Stephenson, Corey R. J.
中科院分区：
文献类型：
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作者：
Staveness, Daryl;Sodano, Taylor M.;Stephenson, Corey R. J.
本报告描述了氨基环丙烷通过胺自由基阳离子中间体的均裂引发的形式[3 + 2]环加成的光化学转化为1-氨基降冰片烷。与药物发现中向富含sp（3）基序的现代运动相一致，该策略提供了对这种饱和碳环框架上的多种取代模式的访问，同时提供了强大的官能团耐受性（例如，-OH，-NHBoc）。评价选定的吗啉基1-氨基降冰片烷的代谢稳定性表明，氧化加工的倾向低，没有倾向于反应性代谢产物的形成，这表明1-氨基降冰片烷的潜在生物电子等排作用。连续流处理允许在克规模上进行有效操作，为转化为工业相关规模提供了希望。这种方法只需要低负载的市售可见光活性光催化剂和简单的盐;因此，它忠实于可持续性目标，同时容易提供饱和的构建模块，可以降低药物开发计划中的代谢敏感性。
This report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp(3)-rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.