23094-31-7Relevant articles and documents
Efficient synthesis of 1,4-thiazepanones and 1,4-thiazepanes as 3d fragments for screening libraries
Pandey, Anil K.,Kirberger, Steven E.,Johnson, Jorden A.,Kimbrough, Jennifer R.,Partridge, Danika K. D.,Pomerantz, William C. K.
supporting information, p. 3946 - 3950 (2020/06/08)
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.
Metal Ion Effects in Intramolecular Reactions. Effects of Divalent Metal Ions on Intramolecular Acetamido Group Participation in Ester Hydrolysis
Fife, Thomas H.,Przystas, Theodore J.,Pujari, Mahesh P.
, p. 8157 - 8163 (2007/10/02)
The hydrolysis reactions of a series of esters of α-acetamidocinnamic acid proceed with formation of an oxazolinone intermediate.In 50percent dioxane-H2O (v/v) at 50 deg C, an oxazolinone can be observed spectrophotometrically in the OH- catalyzed cyclization reactions of the α-acetamido-substituted esters with leaving groups of pKa 12.4 or less.In comparison with the OH- catalyzed hydrolysis of the corresponding cinnamate esters, the rate enhancement due to the presence of the acetamido group is a factor of 200 with the trifluoroethyl ester and increases to 2x1E6 with the p-nitrophenyl ester.The plot of log kOH vs ?, the Hammett substituent constant, is linear and has a slope (ρ) of 2.7 (1.8 when ?- is employed) for the cyclization reactions of the phenolic esters, but the ρ value is only 1.4 for the OH- catalyzed hydrolysis of the corresponding cinnamates.The slope of log kOH vs the pKa of the leaving group for the cyclization of the α-acetamidocinnamic acid derivatives, βlg, is -0.9.Thus, there must be considerable C-O bond breaking in the critical transition state for oxazolinone formation.In H2O as the solvent, 6-carboxy-2-pyridylmethyl α-(N-acetylamino)cinnamate and the corresponding 2-pyridylmethyl derivative cyclize rapidly to the oxazolinone with KOH (5xE4)-fold larger than that for hydrolysis of 2-pyridylmethyl cinnamate, even though the leaving group is an aliphatic alcohol.There is significant metal ion catalysis in the cyclization reactions with Cu2+, Ni2+, Co2+ or Zn2+.The binding of the metal ions to the 6-carboxy-substituted derivative is very strong, and saturation occurs at metal ion concentrations less than 0.01 M.A saturating concentration of Cu2+ (0.001 M) enhances the rate of cyclization by a factor of 5x1E4.Thus, the total rate enhancement provided by bifunctional catalysis (Cu2+ and the neighboring acetamido group) is 1E9-fold.Metal ion binding to 2-pyridylmethyl α-(N-acetylamino)cinnamate is weak, but nevertheless, the second-order rate constants kOH are similar to those of the 6-carboxy-substituted ester at equal metal ion concentrations.The metal ions must exert their catalytic effect by stabilizing the leaving group alcohol in the transition state.This appears to be a general mechanism for metal ion catalysis of reactions in which C-O bond breaking is the rate-determining step.
