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.
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.
Journal
Current Organocatalysis