Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery
Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery
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DOI：
10.1002/ejoc.201900847
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发表时间：
2019-07-29
影响因子：
2.8
通讯作者：
Spring, David R.
中科院分区：
文献类型：
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作者：
King, Thomas A.;Stewart, Hannah L.;Spring, David R.
近年来，制药业受益于基于片段的药物发现(FBDD)取得的进展，目前有30多种片段衍生药物上市或正在进行临床试验。基于片段的药物发现的成功完全取决于所使用的片段筛选文库的组成。杂环在市售药物中普遍存在，因为它们在提供结合作用方面发挥了作用；因此，杂环片段是FBDD文库的重要组成部分。目前的筛选文库主要是由扁平的、富含sp(2)的化合物主导的，主要是因为它们的合成可操作性，尽管更多的三维支架显示了优越的物理化学性质。在这里，我们报告了一系列生物相关的、片段状杂环螺环的分步高效路线。在复杂性生成[3+2]-环加成反应中探索了使用缺电子和富电子的2原子给体，以商业上可用的原料为原料，分3步提供产品。所得到的化合物从合成开始就通过包括合成手柄为进一步的片段精加工做好准备。
In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp(2)-rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three-dimensional scaffolds. Herein, we report step-efficient routes to a number of biologically relevant, fragment-like heterocyclic spirocycles. The use of both electron-deficient and electron-rich 2-atom donors was explored in complexity-generating [3+2]-cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses.