Diastereospecific entry to pyrrolidinyldispirooxindole skeletons via three-component 1,3-dipolar cycloadditions
Graphical abstract
Introduction
Spirooxindoles have recently attracted considerable attention because of their prevalence in a variety of pharmaceuticals and natural alkaloids that possess prominent bioactivities including antidiabetic, anticancer, antitubercular, as well as antibacterial properties (Scheme 1a) [1]. As a subclass of spirooxindoles, by virtue of merging spirooxindole and pyrrolidine units, 3,3′-pyrrolidinyldispirooxindoles are thought to possess unique bioactivities and gradually become appealing synthetic targets. Nevertheless, the demanding steric effect of vicinal quaternary carbon centres and the rigidity of the framework pose intimidating hurdle in the advance of their syntheses. In this context, unceasing efforts to develop efficient approaches to construct dispirooxindole, especially bearing fused heterocycles, are highly desirable.
1,3-Dipolar cycloaddition (1,3-DC) of azomethine ylides and dipolarophiles is a powerful tool for the assembly of biologically active five-membered heterocycles [2]. Given the fact that azomethine ylides could be facilely generated in situ from isatins with various primary or secondary amines, 1,3-dipolar cycloaddition reactions involving 3-oxindole-derived azomethine ylides have thus became one of the most step-/atom-economical and straightforward protocols for the construction of dispirooxindoles, especially for 3,3′-pyrrolidinyldispirooxindoles. Not surprisingly, previously reported methods for assembling.
3,3′-pyrrolidinyldispirooxindole skeletons mainly relied on the 1,3-dipolar cycloaddition of methyleneindolinones with isatin-derived azomethine ylides [3]. In particular, multicomponent 1,3-dipolar cycloadditions of azomethine ylides through the decarboxylative condensation of α-amino acids with isatins are gaining intensive interest, due to the high efficiency in the generation of the corresponding azomethine ylides (Scheme 1b). In 2004, Bergman's group reported an elegant three-component reaction between isatin, amino acids, and dipolarophiles at high temperature [4]. Thereafter, diverse amino acids, such as sarcosine and proline, were employed to react with different methyleneindolinones, affording a range of novel dispiropyrrolidine bisoxindole derivatives [5]. Unfortunately, despite the thorough investigation of decarboxylative condensation between isatins and secondary α-amino acids [6], primary amino acids have not received enough attention in the field as the decarboxylation process in the formation of azomethine ylide is remarkably sluggish for primary amino acid [[1]e), [7]]. Noticeably, primary amino acids are abundant and environmentally benign feedstocks for synthetic chemistry. Therefore, aiming to fully taking advantage of the library of amino acids and filling the gap of biologically important dispiropyrrolidine bisoxindoles, the 1,3-DC reactions applicable to wide range of primary amino acids under mild reaction conditions are urgent to be explored. Herein, we disclose 1,3-dipolar cycloadditions of methyleneindolinones with azomethine ylides that generated in situ from diverse primary amino acids with isatins in MeOH, without adding any additives or catalysts (Scheme 1b). A series of primary amino acids were successfully employed in the developed protocol, significantly expanding the diversity and complexity of the library of dispirooxindole-pyrrolidines.
Section snippets
Results and discussion
Firstly, a model reaction of N-benzyl-protected isatin 1a (0.2 mmol), phenylalanine 2a (0.4 mmol) and methyleneindolinone 3a (0.2 mmol) was surveyed (Table 1). Discouragingly, various solvents were evaluated and no apparent product was observed (entries 1–4). To our delight, the reaction successfully yielded the desired dispiropyrrolidinyl bisoxindole 4aaa with good yield and excellent diastereospecificity in MeOH (entry 5). Other solvents such as DMSO and DMF also furnished the desired product
Conclusion
In conclusion, facile construction of 3,3′-pyrrolidinyldispirooxindoles with potential biological activity has been efficiently accomplished via a multicomponent 1,3-dipolar cycloadditions of methyleneindolinones 3 with azomethine ylides generated in situ from isatins and a series of primary amino acids under extremely mild reaction conditions. The corresponding adducts bearing vicinal spiroquaternary stereocenters were obtained in high yields (up to 99% yield) with excellent
General
Unless otherwise noted, all the reagents were purchased from commercial suppliers and used without further purification. 1H NMR spectra were recorded at 400 MHz. The chemical shifts were recorded in ppm relative to tetramethylsilane and with the solvent resonance as the internal standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, h = sextet), coupling constants (Hz), integration. 13C NMR data were collected at
Acknowledgments
We gratefully acknowledge the financial support from National Natural Science Foundation of China (21576296, 21776318 & 81703365), China Postdoctoral Science Foundation (2017M610504) and Central South University.
References (8)
- et al.
J. Comb. Chem.
(2010)et al.Tetrahedron
(2017) - et al.
J. Heterocycl. Chem.
(2018)et al.Org. Biomol. Chem.
(2015)et al.Synth. Commun.
(2018)et al.Synth. Commun.
(2014) - et al.
Org. Lett.
(2007)et al.Acc. Chem. Res.
(2011)et al.Bioorg. Med. Chem. Lett
(2013)et al.Chem. Rev.
(2012)et al.Tetrahedron Lett.
(2012) - et al.
Tetrahedron
(2007)et al.Org. Lett.
(2005)et al.Chem. Rev.
(2005)et al.Chem. Rev.
(2006)et al.Tetrahedron
(2009)et al.Tetrahedron Lett.
(2009)et al.Eur. J. Org Chem.
(2004)et al.Tetrahedron
(2002)et al.Angew. Chem. Int. Ed.
(2006)et al.Angew. Chem. Int. Ed.
(2006)et al.J. Org. Chem.
(2002)et al.Angew. Chem. Int. Ed.
(2005)
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