2-Azetidinone, the simplest β-lactam

A β-lactam (beta-lactam) ring is a four-membered lactam.[1] (A lactam is a cyclic amide). It is named as such because the nitrogen atom is attached to the β-carbon relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.

Clinical significance

Penicillin core structure

The β-lactam ring is part of the core structure of several antibiotic families, the principal ones being the penicillins, cephalosporins, carbapenems, and monobactams, which are, therefore, also called β-lactam antibiotics. Nearly all of these antibiotics work by inhibiting bacterial cell wall biosynthesis. This has a lethal effect on bacteria. Bacteria do, however, contain within their populations, in smaller quantities, bacteria that are resistant against β-lactam antibiotics. They do this by expressing one of many β-lactamase genes. More than 1,000 different β-lactamase enzymes have been documented in various species of bacteria.[2] These enzymes vary widely in their chemical structure and catalytic efficiencies.[2] When bacterial populations have these resistant subgroups, treatment with β-lactam can result in the resistant strain becoming more prevalent and therefore more virulent.

History

The first synthetic β-lactam was prepared by Hermann Staudinger in 1907 by reaction of the Schiff base of aniline and benzaldehyde with diphenylketene[3][4] in a [2+2] cycloaddition:

Up to 1970, most β-lactam research was concerned with the penicillin and cephalosporin groups, but since then, a wide variety of structures have been described.[5]

Synthesis

The Breckpot Synthesis

  • The synthesis of substituted β-lactams from the cyclization of beta amino acid esters using the Grignard reagent [1]
Breckpot Synthesis

Reactivity

Due to ring strain, β-lactams are more reactive to hydrolysis conditions than are 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 the aplanarity of the system. The nitrogen atom of an ideal amide is sp2-hybridized due to resonance, and sp2-hybridized atoms have trigonal planar bond geometry. As a pyramidal bond geometry is forced upon the nitrogen atom by the ring strain, the resonance of the amide bond is reduced, and the carbonyl becomes more ketone-like. Nobel laureate Woodward described a parameter h as a measure of the height of the trigonal pyramid defined by the nitrogen (as the apex) 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.[6] Monobactams have h values between 0.05 and 0.10 angstroms (Å). Cephems have h 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.[7]

Other applications

A new study has suggested that β-lactams can undergo ring-opening polymerization to form amide bonds, to become nylon-3 polymers. The backbones of these polymers are identical to peptides, which offer them biofunctionality. These nylon-3 polymers can either mimic host defense peptides or act as signals to stimulate 3T3 stem cell function.

Antiproliferative agents that target tubulin with β-lactams in their structure have also been reported.[8][9]

See also

References

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External links

  • Synthesis of β-lactams