Chemical Capabilities, Analytical & Purification, Global Discovery Chemistry, Janssen Research and Development, Janssen-Cilag, S.A., C/Jarama 75A, E-45007 Toledo, Spain.
Org Lett. 2023 Feb 10;25(5):771-776. doi: 10.1021/acs.orglett.2c04226. Epub 2023 Feb 1.
Strained bicyclic substructures such as bicyclo[1.1.1]pentylamines (BCPAs) are increasingly targeted in medicinal chemistry as arylamine bioisosteres. Here, we leverage high-throughput automated synthesis to rapidly develop library-amenable reaction conditions and maximize design space to expand access to BCPAs. This new protocol relies on a copper-mediated C-N coupling approach and uses accessible and bench-stable iodo-BCP building blocks. Its applicability has been exemplified by incorporating BCPs in drug-like compounds, providing straightforward access to a library of valuable aniline-like isosteres.
受到张力的双环亚结构，如双环[1.1.1]戊胺（BCPAs），作为芳基胺生物等排体，在药物化学中越来越受到关注。在这里，我们利用高通量自动化合成技术快速开发库相容的反应条件，并最大限度地扩大设计空间，以扩大 BCPAs 的获取途径。这种新的方法依赖于铜介导的 C-N 偶联方法，并使用易于获得和在实验台上稳定的碘代 BCP 构建块。该方法的适用性已通过将 BCP 纳入类似药物的化合物中得到证明，为有价值的苯胺类似物等排体库提供了直接的获取途径。
