The Chemistry of 2‐Azetidinones (β‐Lactams)

Abstract

The large number of recent reports on b-lactam chemistry demonstrates the increasing interest in this important class of compounds. Monocyclic b-lactams frequently serve as precursors for the synthesis of classical bicyclic b-lactam antibiotics. The cyclic 2-azetidinone skeleton has been extensively used as a template on which to build the heterocyclic structure fused to the four-membered ring, using the chirality and functionalization of the b-lactam nucleus as a stereocontrolling element. The discovery of nonclassical b-lactam antibiotics, such as monobactams and nocardicins, coupled with ever-growing new applications such as enzyme inhibition has triggered a renewed interest in the building of new monocyclic b-lactam derivatives. Besides the utility of b-lactams as biologically active agents, they are used as intermediates in a-and b-amino acid synthesis, as well as building blocks for alkaloids, heterocycles, taxoids and other types of compounds of biological and medicinal interest. Physicochemical Data Computational ChemistryTheoretical studies show that b-lactams are weaker bases, in the gas phase, than acyclic amides [1]. The attenuation of basicity upon cyclization is stronger than that found for cyclic ketones of similar size due to the existence of a negative hyperconjugation effect that is present in b-lactams but not in cyclic ketones. Ab initio calculations indicate that both b-lactams and acyclic amides are oxygen bases, but the gap between the oxygen and nitrogen intrinsic basicities is much smaller in the former due to the aforementioned cyclization effects. This decrease of the oxygen Modern Heterocyclic Chemistry, First Edition. Edited

Zidovudine-β-Lactam Pronucleoside Strategy for Selective Delivery into Gram-Negative Bacteria Triggered by β-Lactamases

“…Due to the structural relevance of the 2-azetidinone core, retrosynthetic analyses have been extensively studied in the literature. Numerous synthetic pathways are available according to the desired substitutions on the β-lactam ring . We explored several of them, such as the Reformatsky reaction, β-amino acid intramolecular cyclization, and the Mitsunobu reaction.…”

“…Numerous synthetic pathways are available according to the desired substitutions on the βlactam ring. 41 We explored several of them, such as the Reformatsky reaction, β-amino acid intramolecular cyclization, and the Mitsunobu reaction. Unfortunately, most of them failed at the β-lactam cyclization step.…”

Palladium-Catalyzed, Multicomponent Approach to β-Lactams via Aryl Halide Carbonylation

“…This typically relies upon the initial generation of a carboxylic acid precursor to ketenes (e.g., acid chlorides, Scheme a). A number of alternative approaches to β-lactam synthesis have been devised, including many that employ transition metal catalysis or multicomponent reactions. − Examples of these include catalytic ketene cycloadditions, carbonylations, alkyne–nitrone cycloaddition (Kinugasa reaction), imine-α-haloketone condensation (Gilman–Speeter reaction), and the use of the Petasis–Ugi reaction . Our own research group has developed a variant of this reaction involving the palladium-catalyzed carbonylation of α-chloroamides .…”

An Expeditious Iodine-Catalyzed Synthesis of 3-Pyrrole-substituted 2-Azetidinones

“…Since Fleming’s discovery of penicillin from the mould Penicillium notatum in 1928, β-lactam antibiotics remain as one of the most important contributions of science to mankind. The 2-azetidinone (commonly known as β-lactam) ring system is the basic structural feature of a number of broad spectrum β-lactam antibiotics, including penicillins, cephalosporins, carbapenems, nocardicins, monobactams, clavulanic acid, sulbactams and tazobactams, which have been widely used as therapeutic agents to treat bacterial infections and several other diseases [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. The discovery of the nocardicins and monobactams has demonstrated for the first time that β-lactams do not require a conformationally constrained bicyclic structure to possess pharmacological activities, suggesting that the medicinal activity is strictly correlated to the presence of a suitably functionalized 2-azetidinone ring.…”