Reactions of 5-aryl-4-acyl-1-(4-hydroxyphenyl)-3-hydroxy-3-pyrrolin-2-ones with arylamines

Design of Drug‐Like Protein–Protein Interaction Stabilizers Guided By Chelation‐Controlled Bioactive Conformation Stabilization

“…Reaction of rac ‐ 2 with aqueous ammonia in acetic acid under microwave heating afforded only vinylogous amide rac ‐ 6 in 20 % yield, with no rac ‐ 9 observed (Scheme ). This contrasts with literature reports that 4‐aroyl substituents favor regiospecific endocyclic nucleophilic attack by sterically unencumbered amines to afford the regioisomers corresponding to 9 . Reaction of rac ‐ 2 with p ‐methoxybenzylamine under microwave heating afforded rac ‐ 7 (6 %) and rac ‐ 8 (26 %).…”

“…This contrasts with literature reports that 4-aroyl substituents favor regiospecific endocyclic nucleophilic attack by sterically unencumbered amines to afford the regioisomers corresponding to 9. [35][36][37][38][39][40] Reaction of rac-2 with p-methoxybenzylamine under microwave heating afforded rac-7 (6%) and rac-8 (26%). Removal of the PMB group of rac-8 using TFA afforded rac-9 in 53% yield.…”

Pyrrolidinodiones in Enol-Ugi, Enol-Passerini, and Anomalous Enol-Passerini Condensations

“…Importantly, structure-based design has recently identified 1,5-dihydropyrrol-2-ones containing oxygen and nitrogen substituents in position 3 as potent inhibitors of p53-MDM2 protein-protein interactions, which proved selectively active against tumor cells with deleted p53 and tumor xenograft models [5]. Although 3-substitued pyrrolidinones are readily accessible by the nucleophilic substitution on 2,3-diones [6][7][8][9], rather harsh conditions are required and only simple oxygen and nitrogen groups can be introduced [4,5,10]. Thus, it is crucial to find mild and selective procedures to introduce complex substituents on position 3 of pyrrolidinones.…”

Enols as Feasible Acid Components in the Ugi Condensation

“…To optimize the new reaction, we selected pyrrolidine-2,3-diones with carboxyl substituents on position 4 ( 5 , 6 ; Scheme ), which have drawn our attention as they are in the core of many natural products and drugs. , Importantly, the pyrrolidone scaffold have been demonstrated to be a privileged structure in the design of modulators of protein–protein interactions. , Advantageously, pyrrolidine-2,3-diones ( 5 , 6 ) are readily accessible through three-component reactions of aldehydes ( 15 ), amines ( 16 ) and, alternatively, alkyl oxalacetates ( 17 ), , or acetylenedicarboxylates ( 18 ; Scheme ), which exponentially increases the diversity of products attainable from the Ugi-type condensation. Furthermore, the presence of a stereogenic center at position 5 of the ring could be advantageous, as it would lead to the formation of two readily separable diastereomeric products in the Ugi-type reaction.…”