Journal
ORGANIC LETTERS
Volume 22, Issue 10, Pages 3946-3950Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.orglett.0c01230
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Funding
- NIH Biotechnology training grant [5T32GM008347-23]
- Masonic Cancer Center
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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 alpha,beta-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 alpha,beta-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-19 NMR. This synthesis should provide ready access to diverse 3D fragments for screening libraries.
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