Conjugate Additions of Amines to Maleimides via Cooperative Catalysis

Abstract

A cooperative system comprising of a lithium Lewis acid and amine base significantly enhances the rate of the conjugate addition of a wide array of amines to maleimides. This operationally simple, scalable method provides mono‐addition products in high yields and purity. This conjugation was successfully applied to the kinase inhibitor crizotinib in a chemoselective ligation to create novel fluorescent probe.magnified image

Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

“…33 Similarly, Uno et al presented a system involving lithium as a Lewis acid and an amine base for the addition of a variety of amines to maleimides. 34 For the current research, we used the green chemistry approach presented by Vyborny et al We performed addition of tacrine molecule to maleimide (24) to obtain pyrrolidine-2,5-dione (31) in an 81% isolated yield (Scheme 3). A multistep synthetic procedure was adopted for the conjugate addition of substituted amines to maleimide (24).…”

“…Vybornyi et al reported the addition of heteronucleophiles (NH, SH, and OH) to N -Ar-substituted maleimides using optimized conditions of lithium perchlorate (LiClO 4 ) as a weak Lewis acid and water as a solvent at an elevated temperature (100 °C) . Similarly, Uno et al presented a system involving lithium as a Lewis acid and an amine base for the addition of a variety of amines to maleimides . For the current research, we used the green chemistry approach presented by Vyborny et al We performed addition of tacrine molecule to maleimide ( 24 ) to obtain pyrrolidine-2,5-dione ( 31 ) in an 81% isolated yield (Scheme ).…”

“…Experiments were carried out according to Glassman and White, with some modification. − Briefly, the enzymes COX-1 (10 μL, 0.7–0.8 μg) and COX-2 (300 units/mL) were activated on ice for 5 min with the addition of 50 μL of co-factor solution containing 0.9 mM glutathione, 0.1 mM hematin, and 0.24 mM N , N , N , N -tetramethyl- p -phenylenediamine dihydrochloride (TMPD) in 0.1 M Tris HCl buffer with pH 8.0 for activation. After that, 60 μL of enzyme solution and 20 μL of test samples having various concentrations ranging from 31.25 to 1000 μg/mL were kept at room temperature for 5 min.…”

Pyrocinchonimides Conjugate to Amine Groups on Proteins via Imide Transfer

“…Despite their reputation for exclusive thiol reactivity, maleimides are known to react with other nucleophiles, and especially amines. [63][64][65][66][67] also reacted to a small extent with both KF variants, suggesting a Cys-independent addition occurs at a low level for KF. These 5-F-Pci (38) conjugates cannot be detected or identified by mass spectrometry (MS), indicative of their vanishingly small quantities.…”

Self-assembly using a retro Diels-Alder reaction

“…2, and one that is di cult to attain by using conventional triggering methods, is that it enables generation of reactive functional groups (maleimide and furan) that can be used for further modi cation of the supramolecule. For example, maleimide moieties are well known to form covalent adducts with strong nucleophiles such as thiols and amines via a 1,4-Michael addition reaction 31,32 . Thus, the presence of maleimide functionality in the PDA might allow use of the PDA as a biothiol sensor.…”