In recent years, the application β-Lactams has been extended over their antibacterial properties. They have been used as a carrier for selective oncolytic drugs and as a potential neuro-protective agent. The synthesis of these compounds is specialized, needing specific conditions to produce compounds with the right molecular configurations.
Researchers from The university of Texas Pan-American and Prince Muhammad Bin Fahad University describe an expeditious p -toluene sulphonic acid-catalyzed reaction of racemic azetidine-2,3-diones with optically active hydroxyl proline as a chiral reagent concerning the synthesis of all four possible enantiomers of monocyclic 3-(pyrrol-1-yl)-azetidin-2-ones.
The synthesis of optically active C-3-substituted pyrrole containing azetidine-2-ones is a unique synthetic target. The desired azetidine-2,3-diones could be easily synthesized by following the previously reported methods documented in chemistry literature. The team has been working on developing a 3-(pyrrol-1-yl)-azetidin-2-ones hybrid as the therapeutic relevance of the molecule is surging. The team is using different catalytic approaches to find a suitable molecule.
Azetidine-2,3-dione reacts with trans -4- hydroxy-L-proline in the presence of a catalytic amount of p -toluene sulphonic acid in moist ethanol. The crude mixture is purified following the standard method, which leads the optically active cis -b-lactams and trans -b-lactams 8b appending a pyrrole nucleus at the C-3 position of the b-lactam ring. The absolute configurations of b-lactams were assigned by the researchers based on their optical rotation data. The work establishes that ( S )-configuration at C (4) of a monocyclic b-lactam gives a positive optical rotation.
“We are delighted to notice a similar result is obtained with isomeric cis -hydroxy proline in the formation of a cis and trans isomer respectively,” says Bimal Banik, who leads the research team working on the reaction. A plausible mechanism for the formation of 3-(pyrrol-1-yl)-azetidin-2-ones is rationalized by considering nucleophilic addition reaction of cis/trans -hydroxyproline with the extremely reactive C=O group of the α-keto-b-lactams in the presence of TsOH to afford iminium ion intermediate. The resulting compunds underwent further proton expulsion to give another chiral intermediate in situ . This intermediate presumably gives the chiral intermediate upon stereospecific protonation. The desired chirality is best explained on the basis of DKR (Dynamic Kinetic resolution). Finally, intermediates underwent dehydration-decarboxylation leading to the formation of 3-Pyrrole Substituted β-Lactam products. The team was able to achieve high yields of all four diastereomers of 3-(pyrrol-1-yl)-azetidin-2-ones with high diastereoselectivity in a single-pot operation. “The main advantage for this transformation is getting the desired configuration of the pyrrole ring,” says Banik. The report has been published in Current Organocatalysis .
Current Organocatalysis