This article is about the class of chemical compounds. For the related antibiotics, seeβ-Lactam antibiotic.
2-Azetidinone, the simplest β-lactam
Aβ-lactam (beta-lactam) ring is a four-memberedlactam.[1] Alactam is a cyclicamide, andbeta-lactams are named so because the nitrogen atom is attached to theβ-carbon atom relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone. β-lactams are significant structural units of medicines as manifested in manyβ-lactam antibiotics.[2] Up to 1970, most β-lactam research was concerned with thepenicillin andcephalosporin groups, but since then, a wide variety of structures have been described.[3][4]
The β-lactam ring is part of the core structure of severalantibiotic families, the principal ones being thepenicillins,cephalosporins,carbapenems, andmonobactams, which are, therefore, also calledβ-lactam antibiotics. Nearly all of these antibiotics work by inhibiting bacterialcell wall biosynthesis. This has a lethal effect onbacteria, although any given bacteria population will typically contain a subgroup that isresistant to β-lactam antibiotics.Bacterial resistance occurs as a result of the expression of one of many genes for the production ofβ-lactamases, a class of enzymes that break open the β-lactam ring. More than 1,800 different β-lactamase enzymes have been documented in various species of bacteria.[5] These enzymes vary widely in their chemical structure and catalytic efficiencies.[6] When bacterial populations have these resistant subgroups, treatment with β-lactam can result in the resistant strain becoming more prevalent and therefore more virulent. β-lactam derived antibiotics can be considered one of the most important antibiotic classes but prone to clinical resistance. β-lactam exhibits its antibiotic properties by imitating the naturally occurring d-Ala-d-Ala substrate for the group of enzymes known aspenicillin binding proteins (PBP), which have as function to cross-link the peptidoglycan part of the cell wall of the bacteria.[7]
Many methods have been developed for the synthesis of β-lactams.[10][11][12]
TheBreckpot β-lactam synthesis[13] produces substituted β-lactams by the cyclization of beta amino acid esters by use of aGrignard reagent.[14]Mukaiyama's reagent is also used in modified Breckpot synthesis.[13]
Due toring strain, β-lactams are more readilyhydrolyzed than linear amides or larger lactams. This strain is further increased by fusion to a second ring, as found in most β-lactam antibiotics. This trend is due to the amide character of the β-lactam being reduced by theaplanarity of the system. The nitrogen atom of an ideal amide issp2-hybridized due toresonance, and sp2-hybridized atoms havetrigonal planar bond geometry. As apyramidal bond geometry is forced upon the nitrogen atom by the ring strain, the resonance of the amide bond is reduced, and the carbonyl becomes moreketone-like.Nobel laureateRobert Burns Woodward described a parameterh as a measure of the height of the trigonal pyramid defined by the nitrogen (as theapex) and its three adjacent atoms.h corresponds to the strength of the β-lactam bond with lower numbers (more planar; more like ideal amides) being stronger and less reactive.[15] Monobactams haveh values between 0.05 and 0.10 angstroms (Å). Cephems haveh values in of 0.20–0.25 Å. Penams have values in the range 0.40–0.50 Å, while carbapenems and clavams have values of 0.50–0.60 Å, being the most reactive of the β-lactams toward hydrolysis.[16]
^Gilchrist T (1987).Heterocyclic Chemistry. Harlow: Longman Scientific.ISBN978-0-582-01421-3.
^Fisher, J. F.; Meroueh, S. O.; Mobashery, S. (2005). "Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity".Chemical Reviews.105 (2):395–424.doi:10.1021/cr030102i.PMID15700950.
^Flynn EH (1972).Cephalosporins and Penicillins : Chemistry and Biology. New York and London: Academic Press.
^Hosseyni S, Jarrahpour A (October 2018). "Recent advances in β-lactam synthesis".Organic & Biomolecular Chemistry.16 (38):6840–6852.doi:10.1039/c8ob01833b.PMID30209477.
^Tidwell TT (2008). "Hugo (Ugo) Schiff, Schiff bases, and a century of beta-lactam synthesis".Angewandte Chemie.47 (6):1016–20.doi:10.1002/anie.200702965.PMID18022986.
^Alcaide, Benito; Almendros, Pedro; Aragoncillo, Cristina (2007). "Β-Lactams: Versatile Building Blocks for the Stereoselective Synthesis of Non-β-Lactam Products".Chemical Reviews.107 (11):4437–4492.doi:10.1021/cr0307300.PMID17649981.
^Nangia A, Biradha K, Desiraju GR (1996). "Correlation of biological activity in β-lactam antibiotics with Woodward and Cohen structural parameters: A Cambridge database study".J. Chem. Soc. Perkin Trans.2 (5):943–53.doi:10.1039/p29960000943.
