Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Org Lett. 2020 May 15;22(10):3946-3950. doi: 10.1021/acs.orglett.0c01230. Epub 2020 Apr 29.
1,4-Thiazepanes and 1,4-thiazepanones represent seven-membered ring systems with highly 3D character and are currently underrepresented in fragment screening libraries. A nuclear magnetic resonance (NMR) fragment screen identified 1,4-acylthiazepanes as new BET (bromodomain and extraterminal domain) bromodomain ligands; however, an efficient and readily diversified synthesis for library development has not been reported. Here we report a one-pot synthesis using α,β-unsaturated esters and 1,2-amino thiols to form 1,4-thiazepanones as precursors to 1,4-thiazepanes with high 3D character. This reaction proceeds in reasonable time (0.5-3 h) and in good yield and tolerates a broad scope of α,β-unsaturated esters. Several 1,4-thiazepanes were synthesized by a two-step transformation and were characterized as new BET bromodomain ligands using protein-observed F NMR. This synthesis should provide ready access to diverse 3D fragments for screening libraries.
1,4-噻嗪烷和 1,4-噻嗪酮是具有高度三维特征的七元环系统，目前在片段筛选库中代表性不足。核磁共振（NMR）片段筛选鉴定出 1,4-酰基噻嗪烷作为新型 BET（溴结构域和末端结构域）溴结构域配体；然而，尚未报道用于文库开发的高效且易于多样化的合成方法。在这里，我们报告了一种使用α,β-不饱和酯和 1,2-氨基硫醇一锅合成的方法，形成具有高 3D 特征的 1,4-噻嗪酮作为 1,4-噻嗪烷的前体。该反应在合理的时间（0.5-3 h）内以良好的收率进行，并且对广泛范围的α,β-不饱和酯具有良好的耐受性。通过两步转化合成了几种 1,4-噻嗪烷，并通过蛋白观察 F NMR 将其表征为新型 BET 溴结构域配体。该合成应为筛选文库提供了对各种三维片段的便捷获取途径。
