The era of β-lactam antibiotics, which represent the most important class of drugs against infectious diseases caused by bacteria, began more than fifty years ago with the discovery of penicillin G. Further improvements by isolation and structure elucidation of new natural compounds, and systematic chemical modification of these, is a striking example of to what extent chemistry can contribute to the progress of drug therapy. The complex relationship between structure and activity requires, even today, a largely empirical approach. The minimum structural unit for antibiotic activity had to be revised several times over decades. Both the activated β-lactam ring with an acidic group and the nature and spatial arrangement of the other substituents and rings decisively affect the potency, antibacterial spectrum, pharmacokinetics, and toxicity. Totally synthetic mono- and bicyclic compounds from the series of monobactams, penems, carbapenems, 1-oxacephems, and 1-carbacephems are increasingly joining the classic groups obtained by semisynthesis from 6-amino-penicillanic acid and 7-aminophalosporanic acid.

Recent Developments in the Field of β‐Lactam Antibiotics

Free-radical reactions in the synthesis of alpha -amino acids and derivatives

Ozonolysis chemistry has been used extensively in academic, research, and industrial environments. A review on ozonolysis by Bailey appeared in Chemical Re Viewsnearly 50 years ago, and a significant amount of research has since been published and reviewed. 1-3 Synthetic chemists have many alternative chemical transformations at their disposal, but the ease with which an ozonolysis reaction can be conducted renders it a clean and effective choice for oxidative cleavage of double bonds. The primary concern with ozonolysis chemistry rests on safety issues because the lowmolecular-weight ozonides and peroxides produced are unstable intermediates. These products could form an explosive hazard upon concentration during the workup if methods to detect and safely quench the peroxides are not employed. Scaling an ozonolysis reaction to an industrial level requires a careful assessment of the energetics of the reaction at hand. The mechanism of an ozonolysis reaction has been thoroughly studied, and the Criegee mechanism has been accepted as shown below. 4-6 Generally, ozone is generated from air or oxygen and passed through a cold solution (from 0 to -78 °C) of solvent and substrate until a blue color is observed, indicating destruction of the double bond. Typical solvents include methanol, ethyl acetate, dichloromethane, ethanol, water, and acetic acid. After sparging with nitrogen to dissipate the free ozone, a reductive or oxidative workup can afford a wide variety of products including alcohols, aldehydes, ketones, acids, and amines. Kula has reported conditions that allow for safely performing ozonolysis reactions up to a 500 g scale. 7 Because the high-energy ozonide (also called normal or secondary ozonide or 1,2,4-trioxolane) is formed in nonparticipating solvents, the use of protic solvents such as alcohols or acids is preferred. The resulting alkoxy and acyloxy hydroperoxides are reduced more efficiently and pose less of a safety risk during scale-up. The temperature at which an ozonolysis reaction is typically carried out is -78 °C; however, Kula recommends temperatures between 0 and-20 °C or higher. His reasoning is based on the idea that at higher temperatures the primary ozonide (1,2,3trioxolane or molozonide) will be more likely to smoothly decompose into the corresponding hydroperoxides and disfavor collapse into the 1,2,4-trioxolane. Running the reaction at higher temperatures in participating solvents will promote the formation of hydroperoxide intermediates that can quickly react with the solvent and provide a safer reaction.

Ozonolysis applications in drug synthesis.

Cycloalkenes by intramolecular wittig reaction

Quinazolinones of formulae 1a, 1b, 1c and 1d are disclosed. They are useful for treating cellular proliferative diseases and disorders associated with KSP kinesin activity.

Methods and compositions utilizing quinazolinones

‘7-aminocephalocillanic acid’ 1, an intermediate for the preparation of new β-lactam antibiotics was prepared by transforming the β-lactam carbinol 2a to the phosphorane 9a through several steps. Oxydation of 9a with DMSO/Ac2O led directly to the cyclized ester 11a, which has been converted into 1 by known methods.

Neue β‐Lactam‐Antibiotika. Über die Darstellung der «7‐Aminocephalocillansäure». Modifikationen von Antibiotika, 4. Mitteilung [1]

3-Hydroxy-ceph-3-em-esters 5 a–c, versatile intermediates for the preparation of new β-lactam antibiotics, were obtained by ozonolysis of the corresponding 3-methylidene-esters 3 a–c. Reduction and elimination gave the 3-unsubstituted ester 13; derivatives 16 a–c and 20–22 resulted from O-alkylation. The 3-methoxy-esters 16 a–c were converted into the corresponding acids 23 a–d. Several other transformations of the β-ketoester system are described.

[New beta-lactam antibiotics. Derivatives of 3-hydroxy-7-amino-ceph-3-em-4-carboxylic acid]

The invention concerns 7-amino-ceph-3-em-4-carboxylic acid compounds of the formula ##STR1## wherein R1 a represents hydrogen or an amino protective group R1 A and R1 b represent hydrogen or an acyl group AC, or R1 A and R1 b together denote a bivalent amino protective group, and R2 represents hydrogen or an organic radical R2 A which together with the --C(═O)--O-- grouping forms a protected carboxyl group, or salts such compounds which possess salt-forming groups; these compounds have antibiotic properties.

8-oxo-5-thia-1-azabicyclo(4,2,0)oct-2-ene compounds

New β-lactam antibiotics. Functionalisation of the cephem 3-position with sulfur or nitrogen bearing substituents



The tosylate sulfoxides or mesylates derived from the 3-hydroxy-ceph-3-em esters 1a, b reacted with thiols to give 3-thioethers which were converted into the microbiologically active acids 7a, c, 8a, c 9c, and 13c by known procedures. The 3-methylsulfonyl-derivative 17c was prepared from 6b. The synthesis of the 3-acylamino-ceph-3-em-4-carboxylic acids 23c and 24c is reported.

[New beta-lactam antibiotics. Functionalisation of the cephem 3-position with sulfur or nitrogen bearing substituents (author's transl)].

Two representatives of the yet unknown type of Δ2-cephem-4β-carboxylic acids were prepared. Contrarily to the prediction based on the activity model of Cohen, both acids proved inactive as antibiotics. Possible reasons for this discrepancy are briefly discussed.

Are the known Δ2-cephems inactive as antibiotics because of an unfavourable steric orientation of their 4α-carboxylic group? Synthesis and biology of two Δ2-cephem-4β-carboxylic acids

Riccardo Scartazzini

Papers

Neue β‐Lactam‐Antibiotika. Über die Darstellung der «7‐Aminocephalocillansäure». Modifikationen von Antibiotika, 4. Mitteilung [1]

[New beta-lactam antibiotics. Derivatives of 3-hydroxy-7-amino-ceph-3-em-4-carboxylic acid]

8-oxo-5-thia-1-azabicyclo(4,2,0)oct-2-ene compounds

[New beta-lactam antibiotics. Functionalisation of the cephem 3-position with sulfur or nitrogen bearing substituents (author's transl)].

Are the known Δ2-cephems inactive as antibiotics because of an unfavourable steric orientation of their 4α-carboxylic group? Synthesis and biology of two Δ2-cephem-4β-carboxylic acids