TY - JOUR
T1 - Efficient synthesis of 1,4-thiazepanones and 1,4-thiazepanes as 3d fragments for screening libraries
AU - Pandey, Anil K
AU - Kirberger, Steven E.
AU - Johnson, Jorden A.
AU - Kimbrough, Jennifer R
AU - Partridge, Danika K.D.
AU - Pomerantz, William C.K.
N1 - Funding Information:
We acknowledge the NIH Biotechnology training grant 5T32GM008347-23 and the Masonic Cancer Center for funding.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/5/15
Y1 - 2020/5/15
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.orglett.0c01230
DO - 10.1021/acs.orglett.0c01230
M3 - Article
C2 - 32347732
AN - SCOPUS:85084782816
SN - 1523-7060
VL - 22
SP - 3946
EP - 3950
JO - Organic Letters
JF - Organic Letters
IS - 10
ER -