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. 2023 Nov 15;24(22):16359.
doi: 10.3390/ijms242216359.

Diastereoselective Synthesis of Dispiro[Imidazothiazolotriazine-Pyrrolidin-Oxindoles] and Their Isomerization Pathways in Basic Medium

Alexei N Izmest Ev  1   2 , Dmitry B Vinogradov  1 , Angelina N Kravchenko  1 , Natalya G Kolotyrkina  1 , Galina A Gazieva  1
Affiliations

Diastereoselective Synthesis of Dispiro[Imidazothiazolotriazine-Pyrrolidin-Oxindoles] and Their Isomerization Pathways in Basic Medium

Alexei N Izmest Ev et al. Int J Mol Sci. .

Abstract

Highly diastereoselective methods for the synthesis of two series of regioisomeric polynuclear dispyroheterocyclic compounds with five or six chiral centers, comprising moieties of pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine of linear structure or imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine of angular structure, have been developed on the basis of a [3+2] cycloaddition of azomethine ylides to functionalized imidazothiazolotriazines. Depending on the structure of the ethylenic component, cycloaddition proceeds as an anti-exo process for linear derivatives, while cycloaddition to angular ones resulted in a syn-endo diastereomer. Novel pathways of isomerization for the synthesized anti-exo products upon treatment with sodium alkoxides have been found, which resulted in two more series of diastereomeric dispiro[imidazothiazolotriazine-pyrrolidin-oxindoles] inaccessible with the direct cycloaddition reaction. For the first series, the inversion of the configuration of one stereocenter, i.e., C-4' atom of the pyrrolidine cycle, (epimerization) was established. For the second one, configuration of the obtained diastereomer formally corresponded to the syn-endo approach of the azomethine ylide in the case of cycloaddition to the ethylenic component.

Keywords: [3+2] cycloaddition; azomethine ylides; dispirooxindoles; epimerization; imidazothiazolotriazines; isomerization.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Biologically active natural and synthetic spiropyrrolidineoxindoles.
Scheme 1
Scheme 1
Background and purpose of this work. (A). Zhao Y. et al. [12]; (B). Our previous work [28]; (C). This work.
Scheme 2
Scheme 2
Scope of the [3+2] cycloaddition reaction of compounds 9 with amino acids 7 and isatins 8.
Scheme 3
Scheme 3
The proposed formation mechanism and structure of azomethyne ylide.
Scheme 4
Scheme 4
Theoretically possible [3+2] cycloaddition mechanisms.
Scheme 5
Scheme 5
Modes of approach of the azomethine ylide.
Scheme 6
Scheme 6
Synthesis of two diastereomers 4l and 4m based on (R)-2-[(1-phenylethyl)amino]acetic acid 7e.
Scheme 7
Scheme 7
Isomerization of dispirocompounds 4 into diastereomers 5 and 6. a The ratio of compounds 5 and 6 was determined from the 1H NMR spectrum of the mixture. b Isolated yield.
Scheme 8
Scheme 8
Plausible mechanism of the isomerization of compounds 4 into isomers 6.
Figure 2
Figure 2
Comparison of the 1H NMR spectra of diastereomers 4a, 5a and 6a in the region 3.0–8.3 ppm in DMSO-d6.
Scheme 9
Scheme 9
Scope of the 1,3-dipolar cycloaddition reaction of dipolarophiles 10 with amino acids 7 and isatins 8.
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