| Autor: |
Pandey AK; Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States., Kirberger SE; Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States., Johnson JA; Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States., Kimbrough JR; Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States., Partridge DKD; Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States., Pomerantz WCK; Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States. |
| Abstrakt: |
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 19 F NMR. This synthesis should provide ready access to diverse 3D fragments for screening libraries. |
