Dispirooxindole-β-Lactams: Synthesis via Staudinger Ketene-Imine Cycloaddition and Biological Evaluation

Abstract

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of one-pot Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of functionalization to resulting scaffolds. The dispipooxindoles obtained demonstrated medium cytotoxicity in the MTT test on A549, MCF7, HEK293, and VA13 cell lines, and one of the compounds demonstrated antibacterial activity against E. coli strain LPTD.

Chemical Methods for the Construction of Spirocyclic β-Lactams and Their Biological Importance

“…In search for alternative anticancer medicines, Filatov synthesized trans-dispirooxindole-β-lactams utilizing isatin Schiff's bases in a one-pot Staudinger cycloaddition approach (Scheme 9). 25 They first produced a series of N-aryl-2-oxopyrrolidine-3-carboxylic acids 30 (racemate, 65-87% yield) by reacting cyclopropane-1,1-dicarboxylate with various electrondonating or electron-withdrawing primary amines 29 in acetonitrile under inert conditions at ambient temperature. Following a specific reaction involving these acids and isatin Schiff's bases 31, trans-dispirooxindole-β-lactams 32 (35-62%) were produced in a stereoselective manner.…”

“…Scheme25 Leng's report on diastereoselective [3+1] annulation using oxindolyl azaoxyallyl cationsLeng et al have addressed effective methods of synthesizing spiro[β-lactam]-oxindoles, especially the difficult 3,3'-spiro[βlactam]-oxindole scaffold 102, by employing a new azaoxyallyl cation precursor 100 that has a biologically meaningful spirooxindole motif. Their procedure uses sulfur ylides 101 in an alkaline [3+1] annulation (Scheme 25) 41.…”

Stereoselective synthesis of β-lactams: recent examples

“…Multicomponent cycloaddition reactions have been the most widely employed methods in order to obtain β-lactam derivatives, highlighting the synthesis based on the Staudinger ketene-imine cycloaddition. 2,[28][29][30][31][32][33] This section discusses selected recent examples of metal-free stereoselective cycloaddition syntheses of β-lactams.…”

Access to 2-Oxoazetidine-3-carboxylic Acids Derivatives via Thermal Microwave-Assisted Wolff Rearrangement of 3-Diazotetramic Acids in the Presence of Nucleophiles

“…The 2-oxoazetidine-3-carboxylic acid derivatives (mainly amides) exhibit various types of biological activity, among which the following can be highlighted: inhibition of β-lactamases, [4,5] antitubercular properties, [6] antiproliferative and antibacterial activity, [7] herbicidal properties, [8,9] inhibition of neutral amino acid transporter (SLC6A19). [10] Hence, developing new synthetic methods to create structurally diverse 2-oxoazetidine-3-carboxylic acid derivatives is a highly valuable endeavour that could have a positive impact on the future drug discovery.…”