Efficient Synthesis of 1,4-Thiazepanones and 1,4-Thiazepanes as 3D Fragments for Screening Libraries

• Published in: Organic letters Vol. 22; no. 10; pp. 3946 - 3950
• Main Authors: Pandey, Anil K, Kirberger, Steven E, Johnson, Jorden A, Kimbrough, Jennifer R, Partridge, Danika K. D, Pomerantz, William C. K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.05.2020; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Drug Discovery; Esters - chemistry; Ligands; Magnetic Resonance Spectroscopy; Molecular Structure; Physical Sciences; Protein Domains; Proteins - chemistry; Science & Technology; Small Molecule Libraries - chemistry; DISTRIBUTIONS; THIOLS; ACCESS; MOLECULES
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/acs.orglett.0c01230

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 19F NMR. This synthesis should provide ready access to diverse 3D fragments for screening libraries.