Chemistry:Beta-lactam

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Short description: Family of chemical compounds
2-Azetidinone, the simplest β-lactam

A beta-lactam (β-lactam) ring is a four-membered lactam.[1] A lactam is a cyclic amide, and beta-lactams are named so because the nitrogen atom is attached to the β-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 many β-lactam antibiotics[2] 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.[3][4]

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, although any given bacteria population will typically contain a subgroup that is resistant to β-lactam antibiotics. Bacterial resistance occurs as a result of the expression of one of many genes for the production of β-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 as penicillin binding proteins (PBP), which have as function to cross-link the peptidoglycan part of the cell wall of the bacteria.[7]

The β-lactam ring is also found in some other drugs such as the cholesterol absorption inhibitor drug Ezetimibe.

Synthesis

The first synthetic β-lactam was prepared by Hermann Staudinger in 1907 by reaction of the Schiff base of aniline and benzaldehyde with diphenylketene[8][9] in a [2+2] cycloaddition (Ph indicates a phenyl functional group):

StaudingerLactam.svg

Many methods have been developed for the synthesis of β-lactams.[10][11][12]

The Breckpot β-lactam synthesis[13] produces substituted β-lactams by the cyclization of beta amino acid esters by use of a Grignard reagent.[14] Mukaiyama's reagent is also used in modified Breckpot synthesis.[13]

Breckpot synthesis

Reactions

Due to ring strain, β-lactams are more readily hydrolyzed 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 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 Robert Burns 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.[15] 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.[16]

See also

References

  1. ↑ Heterocyclic Chemistry. Harlow: Longman Scientific. 1987. ISBN 978-0-582-01421-3. 
  2. ↑ 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. PMID 15700950. 
  3. ↑ Cephalosporins and Penicillins : Chemistry and Biology. New York and London: Academic Press. 1972. 
  4. ↑ "Recent advances in β-lactam synthesis". Organic & Biomolecular Chemistry 16 (38): 6840–6852. October 2018. doi:10.1039/c8ob01833b. PMID 30209477. 
  5. ↑ "In silico serine β-lactamases analysis reveals a huge potential resistome in environmental and pathogenic species". Scientific Reports 7: 43232. February 2017. doi:10.1038/srep43232. PMID 28233789. Bibcode: 2017NatSR...743232B. 
  6. ↑ "Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor". Proceedings of the National Academy of Sciences of the United States of America 109 (29): 11663–8. July 2012. doi:10.1073/pnas.1205073109. PMID 22753474. Bibcode: 2012PNAS..10911663E. 
  7. ↑ "Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine". Proceedings of the National Academy of Sciences of the United States of America 54 (4): 1133–41. October 1965. doi:10.1073/pnas.54.4.1133. PMID 5219821. Bibcode: 1965PNAS...54.1133T. 
  8. ↑ "Hugo (Ugo) Schiff, Schiff bases, and a century of beta-lactam synthesis". Angewandte Chemie 47 (6): 1016–20. 2008. doi:10.1002/anie.200702965. PMID 18022986. 
  9. ↑ "Zur Kenntniss der Ketene. Diphenylketen". Justus Liebigs Ann. Chem. 356 (1–2): 51–123. 1907. doi:10.1002/jlac.19073560106. https://zenodo.org/record/1427571. 
  10. ↑ 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. PMID 17649981. 
  11. ↑ Hosseyni, Seyedmorteza; Jarrahpour, Aliasghar (2018). "Recent advances in β-lactam synthesis" (in en). Organic & Biomolecular Chemistry 16 (38): 6840–6852. doi:10.1039/C8OB01833B. ISSN 1477-0520. PMID 30209477. http://xlink.rsc.org/?DOI=C8OB01833B. 
  12. ↑ Pitts, Cody Ross; Lectka, Thomas (2014-08-27). "Chemical Synthesis of β-Lactams: Asymmetric Catalysis and Other Recent Advances" (in en). Chemical Reviews 114 (16): 7930–7953. doi:10.1021/cr4005549. ISSN 0009-2665. PMID 24555548. https://pubs.acs.org/doi/10.1021/cr4005549. 
  13. ↑ 13.0 13.1 "Breckpot β-Lactam Synthesis" (in en), Comprehensive Organic Name Reactions and Reagents (Hoboken, NJ, USA: John Wiley & Sons, Inc.): pp. conrr115, 2010-09-15, doi:10.1002/9780470638859.conrr115, ISBN 978-0-470-63885-9, http://doi.wiley.com/10.1002/9780470638859.conrr115, retrieved 2021-02-04 
  14. ↑ "Breckpot Synthesis". http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/breckpot.htm. 
  15. ↑ "Penems and related substances". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 289 (1036): 239–50. May 1980. doi:10.1098/rstb.1980.0042. PMID 6109320. Bibcode: 1980RSPTB.289..239W. 
  16. ↑ "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. 1996. doi:10.1039/p29960000943. 

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