An Approach to a New Type of Spiroheterocyclic Framework: Sterically Hindered Pyrrolidines with Three Spiro‐Fused Oxindole, Imidazothiazolotriazine, and Succinimide Moieties

A highly diastereoselective synthetic strategy for the construction of sterically hindered trispiro[imidazo[4,5‐ e ]thiazolo[3,2‐ b ][1,2,4]triazine‐6,3′‐pyrrolidine‐2′,3″‐indoline‐4′,3‴‐pyrrolidine] derivatives with three adjacent spiro‐nodes has been developed. The transformation chain includes (3 + 2) cycloaddition of azomethine ylide generated in situ from sarcosine and isatin to the exocyclic double bond of imidazothiazolotriazines, containing two ester groups in geminal substituents; subsequent alkaline hydrolysis of one of the ester groups in the resulting dispirocompounds; and formation of a spiro‐cojugated succinimide fragment with involvement of the carboxyl and ester functions under treatment with primary amine. Intermediate dispirocyclic compounds with ester and amidomethyl substituents were also isolated in good yields. Dispirocompounds with two amide functions were synthesized from the methoxycarbonyl(carboxymethyl)substituted precursors and amines. Since dispiroindolinones are efficient p53‐MDM2 interaction inhibitors, we calculated binding affinity of synthesized trispirocompounds to MDM2 protein through molecular docking. The structure (2′ R ,3a S ,4′ S ,6 R ,9a R )‐ 9j (−8.12 kcal/mol) containing a hydroxybutyl substituent in the succinimide fragment, as well as compounds (2′ S ,3a R ,4′ R ,6 S ,9a S ) ‐9k,l and both enantiomers of 9d with bulky phenyl, benzyl, and hexyl groups (binding energy values from −7.80 to −7.87 kcal/mol), showed the highest affinity among compounds 9 . The molecular docking data allow us to identify the most promising products for further biological testing.