Open AccessEfficient Synthesis of 1,4-Thiazepanones and 1,4-Thiazepanes as 3D Fragments for Screening Libraries
Author(s) -
Anil K. Pandey,
Steven E. Kirberger,
Jennifer J. Johnson,
Jennifer R Kimbrough,
Danika K. D. Partridge,
William C. K. Pomerantz
Publication year - 2020
Publication title -
organic letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.94
H-Index - 239
eISSN - 1523-7060
pISSN - 1523-7052
DOI - 10.1021/acs.orglett.0c01230
Subject(s) - bromodomain , chemistry , fragment (logic) , yield (engineering) , combinatorial chemistry , ring (chemistry) , stereochemistry , organic chemistry , computer science , biochemistry , dna , materials science , metallurgy , histone , programming language
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.