Highly Stereoselective Synthesis of Saccharin-Substituted β-Lactams via in Situ Generation of a Heterosubstituted Ketene and a Zwitterionic Intermediate as Potential Antibacterial Agents

Abstract

Highly stereoselective synthesis of saccharin derivatives containing functionalized 2-azetidinone moiety was achieved starting from saccharin as an available precursor. The approach to these valuable heterocyclic scaffolds involves a formal [2π + 2π] cycloaddition between Schiff bases and the saccharinylketene as a novel ketene which was generated in situ and an electrocyclic reaction of a zwitterionic intermediate. The identification of the ketene was confirmed by reaction with the stable free radical TEMPO (TO•). Also, the antimicrobial activities of some new substituted saccharin against nine standard bacteria, four bacteria which were isolated from clinical samples and one yeast, were evaluated.

Recent advances in ketene chemistry

“…Saccharin-substituted ketene 189, generated by carboxylic acid dehydration with Mukaiyama's reagent 186, reacted with imines to produce saccharin-substituted β-lactams, including 190 (Scheme 80), which was tested for biological activity. 120 Mukaiyama's reagent also was used to generate other ketenes for -lactam formation. Ketene 189 generated similarly also reacted with the stable free radical TEMPO forming 191, confirming the identity of the free ketene (Scheme 80).…”

“…Ketene 189 generated similarly also reacted with the stable free radical TEMPO forming 191, confirming the identity of the free ketene (Scheme 80). 120 The new triflyl-substituted ketene 192, generated by thermal diazoketone Wolff rearrangement, gives [2+2] cycloaddition with imines forming the corresponding substituted -lactams (Scheme 81).…”

DFT Calculations and Statistical Mechanics Applied to Isomerization of Pseudosaccharins

“…The properties of the pseudosaccharins can be modified depending on which structures are combined with saccharin. In the case of tetrazole-saccharin, the properties of tetrazole, which can be very reactive, have been combined with saccharin, resulting in a greater stability of the tetrazole [12]. Furthermore, the combination of an allyl group with saccharin can also form compounds with the properties mentioned in previous paragraphs.…”

“…This can lead to challenges in the characterization of these compounds, since there could be a mixture of isomers whose population can become significant during the synthesis. As a result, there are signals in spectrophotometry [4,12,13] that cannot be associated with a precise isomer. Theoretical analysis can ease to obtain the different spectra of the possible isomers and the spectra could be weighted by a number or parameter, for example, a calculated molar fraction.…”

Exploring the Photophysical and Photochemical Properties of N-(Thioalkyl)-saccharins as an Alternative Route to the Synthesis of Tricyclic Sultams

“…Their derivatives are important pharmaceuticals with a broad spectrum of biological activities and have been used as inhibitors of kinase 2 , human mast cell tryptase 3 and tyrosinase 4 , histone deacetylase 5 , α1a and α1c adrenergic receptor antagonists 6 , antianxiety and antibacterial agents. 7 More recently it has been shown that saccharin and saccharin-based compounds selectively bind to tumor-associated carbonic anhydrases. 8 Furthermore, saccharin forms salts with different active pharmaceutical ingredients resulting in highly water-soluble saccharinate, which can act as a potent sweetener able to mask the bitter taste of many drugs.…”