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

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

Journal

European Journal of Organic Chemistry
ISSN: 1434-193X , E-ISSN: 1099-0690

Output data

Year: 2026, Article number : e70640, Pages count : DOI: 10.1002/ejoc.70640

Authors

Streltsov Andrey A. ¹ , Izmest’ev Alexei N. ¹ , Kolotyrkina Natalya G. ¹ , Gazieva Galina A. ¹

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences Moscow Russia

A highly diastereoselective synthetic strategy for the construction of sterically hindered trispiro[imidazo[4,5-e]thiazolo [3,2-b][1,2,4]triazine-6,30 -pyrrolidine-20,300-indoline-40,3‴-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 (20R,3aS,4 0S,6R,9aR)-9j (−8.12 kcal/mol) containing a hydroxybutyl substituent in the succinimide fragment, as well as compounds (20 S,3aR,40 R,6S,9aS)-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.

Streltsov A.A. , Izmest’ev A.N. , Kolotyrkina N.G. , Gazieva G.A.
An Approach to a New Type of Spiroheterocyclic Framework: Sterically Hindered Pyrrolidines with Three Spiro‐Fused Oxindole, Imidazothiazolotriazine, and Succinimide Moieties
European Journal of Organic Chemistry. 2026. e70640 . DOI: 10.1002/ejoc.70640

Submitted:	Feb 13, 2026
Accepted:	Jun 10, 2026
Published online:	Jun 22, 2026

No identifiers