Regio- and stereoselective synthesis of dispiropyrrolizidines through 1,3-dipolar cycloaddition reaction: Inhibition of KRAS expression

Hooi Xian Lee, Wai Ming Li, Chee Wei Ang, Kerry Reimer, Victor Liu, Brian O. Patrick, Keng Yoon Yeong, Chow H. Lee

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A facile three components (3 + 2) cycloaddition of two novel dispiropyrrolizidines was achieved using (2E)-2-(2-bromobenzylidine)-1-indanone and azomethine ylide that was generated in situ from acenapthenequinone and l-proline. Unprecedented regioselectivity was observed when different reaction times and solvents were used in this cycloaddition, leading to the formation of regioisomers (1S,1′S,2′R,7a'S)-1′-(2-bromophenyl)-5′,6′,7′,7a'-tetrahydro-1′H,2H-dispiro[acenaphthylene-1,3′-pyrrolizine-2′,2′'-indene]-1′',2(3′'H)‑dione (6) and (1S,1′S,2′R,7a'S)-2′-(2-bromophenyl)-5′,6′,7′,7a'-tetrahydro-2H,2′H-dispiro[acenaphthylene-1,3′-pyrrolizine-1′,2′'-indene]-1′',2(3′'H)‑dione (7) with two adjacent spirocarbons through endo/exo approaches. 6 was ascribed to the endo-approach of the S-shaped azomethine ylide while that of 7 was ascribed to the exo-approach of the W-shaped ylide. It was observed that the endo-selectivity of the reaction diminishes with increasing reaction time. Longer reaction time showed exo preference in the cycloaddition reaction. The structures of the cycloadducts were elucidated by NMR and ESI-MS. The regiochemistry and structures of the cycloadducts were confirmed by X-ray crystal structure analysis. Using Western blot analysis, we show that the two novel compounds were capable of down-regulating KRAS expression in SW480 human colorectal cancer cell line.

Original languageEnglish
Article number133177
Number of pages11
JournalJournal of Molecular Structure
Volume1263
DOIs
Publication statusPublished - 5 Sep 2022

Keywords

  • 1,3- dipolar cycloaddition
  • Azomethine ylide
  • Colorectal cancer
  • Dispiropyrrolizidine
  • KRAS expression
  • Regioisomers

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