Cephalosporin

Cephalosporins are a grouping of broad-spectrum, semisynthetic β-lactam antibiotics that currently constitute the most widely prescribed grade of antibiotics and are used to care for diseases acquired past both Gram-positive and Gram-negative bacteria with wide safety margins compared to penicillins.

From: Synthesis of Best-Seller Drugs , 2016

Membrane Science and Technology

Minghui Qiu , ... Weihong Xing , in Comprehensive Membrane Science and Engineering (Second Edition), 2017

1.11.4.3.2 Example: Cephalosprin product

Since cephalosporins were discovered in 1945 by the Italian pharmacologist Giuseppe Brotzu, they have been used to treat a broad range of bacterial infections due to their high efficiency, broad-spectrum antibacterial activity, low toxicity, and resistance to enzymes.

During the product of cephalosporins, hyphas, suspended solids, and macromolecular proteins beginning must be removed from fermentation broth to obtain a clarified solution of cephalosporins. Subsequently, the solution was subjected to refining and drying processes to obtain cephalosporin powders. Due to the thermosensitivity of cephalosporins, the refining process must be operated at a low temperature (0–5°C), which is out of the suitable range for polymer membranes. Therefore, ceramic membrane systems get a promising alternative to obtain a clarified solution of cephalosporins due to their first-class thermal stability. Fig. 18 is an industrial ceramic membrane separation arrangement for the production of cephalosporins, which, with a total membrane area of 422 mtwo, was adult past Jiangsu Jiuwu Loftier-Tech Co. Ltd. In this process, the yield of cephalosporins could exceed 92%.

Fig. 18

Fig. 18. Industrial ceramic membrane separation system for the product of cephalosporins.

 Photo courtesy of Jiuwu.

And then far, more than 400 industrial ceramic membrane systems take been synthetic for biological fermentation treatments in China. It has been constitute that ceramic membrane systems showed many advantages over plate and frame filter systems. A detailed list of items is shown in Table ii .

Table 2. Comparing of ceramic membrane system with plate and frame filter systems in the treatments of biological fermentation

Items Plate and frame filter Ceramic membrane
Flux (50/(m2 h)) xl–80 150–200
Removal of mycelium (%) seventy–85 99
Removal of turbidity (%) eighty–85 99
Membrane cleaning Hard Piece of cake
Stability Poor Good
Equipment investment Low High
Lifetime/year >3 iii–5

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Capillary Electrophoresis—Antibiotics

L. Sánchez-Hernández , 1000.L. Marina , in Reference Module in Chemistry, Molecular Sciences and Chemical Applied science, 2016

Cephalosporins

Cephalosporins comprise a vi-member dihydrothiazine ring fused to the β-lactam portion. The substituents at C 3, Civ, and Cvii are of import factors for their biological activity. 15 The carboxyl group at C4 must be unsubstituted, while the acylamido side chain at C7 is a key group governing largely the hydrophilic/hydrophobic character of these compounds.

Regarding the analysis of cephalosporins, levels of cefaclor, cefadroxil, cefamandole, cefazolin, cefepime, cefixime, cefminox, cefoperazone, cefotoxime, ceftazidime, ceftiofur, ceftizoxime, ceftriaxone, cefuroxime, cephalexin, cephapirin, and cephradine were determined by CZE, EKC, MEKC, MEEKC, bit-CZE, and scrap-CEC with UV detection, except for EKC and MEKC where CfourD and LIF detectors, respectively, were also employed.

These antibiotics accept by and large been separated in basic media using acetate (pH 7.0–8.5), borate (pH 9.0–ix.two), tetraborate (pH 9.0–9.two), phosphate (pH vi.five–6.8), and borate/phosphate (pH nine.1), although when using a MEEKC system, phosphate at pH 2.0 was chosen. SDS was employed as anionic surfactant in all the approaches, though, information technology was fifty-fifty combined with Brij35.

Regarding CEC in microchips (chip-CEC), a packed chip with conventional chromatographic reversed-phase silica particles was used for the separation of three cephalosporins using UV cobweb optic detection positioned directly on the chip. Alternatively, this on-capillary UV detection was investigated equally well in a portable capillary-assembled microfluidic system (chip-CZE) in which the injection was carried out in a microchip device only the electrophoretic separation was performed in a conventional CE capillary. This instrument was applied in the separation of half-dozen cephalosporins and the results were compared with those from a commercial CE system. The electropherograms obtained showed like separation efficiency for both instruments although lower sensitivity was reached with the flake-CE system. This was assigned to the fact that the light leaving the fiber end was not properly focused and scattered on the capillary wall producing college background racket.

Finally, it tin can be highlighted that, among the applications carried out to achieve the analysis of cephalosporins in unlike matrices, nutrient was non included. Moreover, while pharmaceutical formulations did non required a special handling, SPE procedures combined with LVSS injection or with previous Cy5 derivatization were employed for environmental (eg, water) or biological samples (eg, cow plasma).

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Genetics and Molecular Biology of Genes Encoding Cephalosporin Biosynthesis in Microbes

Khusbu Singh , ... Gaurav Raj Dwivedi , in New and Futurity Developments in Microbial Biotechnology and Bioengineering, 2019

ii.2.1 Genetics of Cephalosporin Biosynthesis

Cephalosporin biosynthesis is a complex and multistep process involving v different enzymes encoded by six dissimilar genes which are located in ii different clusters (early on and late) of chromosomes ( Figs. 2.one and 2.2; Table 2.ii). Initially the biosynthesis of cephalosporin in fungi requires three amino acids namely l-valine, 50-α-aminoadipic acid (LAA), and l-cysteine; among them, LAA is regarded as a nonproteinogenic amino acid, which is considered as an intermediary pathway of lysine biosynthesis in fungi. Whereas, in leaner, the conversion of lysine to α-aminoadipic acid semialdehyde is carried out by enzyme lysine-6-aminotransferase (LAT). Piperideine-6-carboxylic acid dehydrogenase (P6C-DH) is responsible for the oxidation of this semialdehyde to LAA (Martín et al., 2010; Coque et al., 1991). Condensation of all the three amino acids is responsible for the development of a tripeptide δ-(l-α-aminoadipyl)–l-cysteinyl–50-valine (ACV) complex with assist of enzyme ACV synthetase (ACVS) (Fig. two.1). This ACVS enzyme is the product of acvA/pcbAB, a solitary constitutional gene (Brakhage, 1998; Martín et al., 2010). Formation of penam nucleus takes place via the elimination of four atoms of hydrogen. Isopenicillin Due north (IPN) possessing weak antibody activity is formed in this step with the assist of enzyme IPN synthase (IPNS). IPNS is the product of the cistron pcbC/ipnA and human action as dioxygenases, which requires ascorbate, oxygen, and Iron2+. Enzyme IPN epimerase (IPNE) gives penicillin N by the isomerization of IPN. Penicillin N is supposed to be the precursor of cephalosporin and cephamycin. Deacetoxycephalosporin C (DAOC) is formed past the action of enzyme DAOC synthetase/DAC hydroxylase, which is encoded by cefEF gene (Brakhage, 1998). This is two-pace process where penicillin Northward is converted first into DAOC and and then into deacetylcephalosporin C (DAC) via a single enzyme. Cephalosporin C is the end product of the biosynthetic pathway of cephalosporin, that is, done past DAC acetyl transferase in which the acetyl grouping is relocated from acetyl CoA (acetyl coenzyme A) to DAC.

Figure two.1. Cephalosporin biosynthetic pathway in A. chrysogenum.

Figure 2.two. Cephalosporin genes organization in A. chrysogenum.

Table 2.2. List of Genes and Corresponding Enzymes Nowadays in A. chrysogenum

Genes/Size in (bp) Enzyme Site of Production Size of the Enzyme (kDa) Substrate for the Enzymes References
pcbAB/acvA ACV synthetase Cytosol 420 50-α-Aminoadipic acid (LAA) Brakhage (1998), Martín et al. (2010), Baldwin et al. (1990), Díez et al. (1990), Gutiérrez et al. (1991)
11,136 l-Cysteine
l-Valine
pcbC/ipnA IPN synthase Cytosol 38 δ-(50-α-Aminoadipyl)-l-cysteinyl-d-valine (ACV tripeptide) Brakhage (1998), Samson et al. (1985)
1014
cefD1 IPN epimerase Peroxisome matrix (microbodies) 71 Isopenicillin N (IPN) Martín et al. (2010), Liras and Martín (2006)
cefD2 –
cefEF DAOC synthetase/DAC hydroxylase Cytosol – Penicillin N Dotzlaf and Yeh (1987), Scheidegger et al. (1984)
996 Deacetoxycephalosporin C (DAOC)
cefG 1332 DAC-acetyltransferase (DAC-AT) Cytosol 49 Deacetylcephalosporin C (DAC) Martín et al. (2010), Evers et al. (2004), Gutiérrez et al. (1992), Van de Kamp et al. (1999), Velasco et al. (1999)

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Antibiotics

Ruben Vardanyan , Victor Hruby , in Synthesis of All-time-Seller Drugs, 2016

2nd-Generation Cephalosporins

2d-generation cephalosporins are more constructive against Gram-negative bacterial species that are resistant to the first-generation cephalosporins. They have proven effective confronting Gram-positive Staphylococcus and Streptococcus bacteria, and some Gram-negative bacteria, including Bacteroides fragilis, H. influenzae, Moraxella catarrhalis, N. meningitidis, N. gonorrhoeae, and some Enterobacteriaceae.

Within the second-generation cephalosporins are ii groups of compounds that differ structurally, in spectrum of activeness, and in side effects. These groups are known every bit the "true" second-generation cephalosporins—cefamandole (xxx.one.twoscore), cefonicid (thirty.1.41), cefuroxime (30.one.42), cefuzonam (30.i.43), cefaclor (30.1.44), cefprozil (xxx.1.45) (Fig. 30.10.), and cephamycins or 7-methoxycephalosporins.

Fig. 30.10. 2d-generation cephalosporins.

Cefoxitin (30.one.46), cefotetan (30.1.47), and cefmetazole (30.1.48) are considered 2d-generation cephalosporins called cephamycins. Insertion of 7α-methoxy group gives resistance to β-lactamases and makes them pharmacologically different from other cephalosporins (Fig. thirty.11.).

Fig. thirty.11. Second-generation cephalosporins—the cephamycins.

The "true" second-generation agents are useful for community-caused infections of the respiratory tract and uncomplicated urinary tract infections. The cephamycin group is useful for mixed aerobic–anaerobic infections of the skin and soft tissues, intraabdominal, and gynecologic infections, and surgical prophylaxis.

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Carboxylic Acrid Derivatives

Robert J. Ouellette , J. David Rawn , in Organic Chemistry (2nd Edition), 2018

22.ten Bioorganic Chemical science

Biochemical Hydrolysis of Penicillin

Penicillins and cephalosporins are two classes of bactericides that comprise a four-membered lactam ring; they are β-lactams ring. Although representatives of both types of compounds were originally isolated from fungi, derivatives are now produced by structural modification in the laboratory. We will focus our attending upon penicillin Chiliad.

Unlabelled Image

Penicillin Grand inhibits the synthesis of bacterial jail cell walls, causing growing cells to flare-up. The enzyme transpeptidase catalyzes reactions that form the cell wall. The enzyme forms a complex with penicillin G, and the carbonyl group reacts with a serine hydroxyl grouping contained in the active site of the enzyme. The first step of the reaction is a germination of a tetrahedral intermediate.

Unlabelled Image

The tetrahedral intermediate then collapses to give an acyl enzyme, which hydrolyzes to requite a penicillinic acid.

Unlabelled Image

Most amides are ineffective acylating agents. Even so, the four-membered band of a β-lactam is strained. Relief of strain provides the driving force for its reaction with the nucleophile at the enzyme agile-site.

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Carboxylic Acid Derivatives

Robert J. Ouellette , J. David Rawn , in Organic Chemical science, 2014

Biochemical Hydrolysis of Penicillin

Penicillins and cephalosporins are two classes of bactericides that contain a iv-membered lactam (a β-lactam). Although representatives of both types of compounds were originally isolated from fungi, derivatives are now produced by structural modification in the laboratory. We will focus our attending upon penicillin G.

Penicillin G inhibits the synthesis of bacterial prison cell walls, causing growing cells to flare-up. The enzyme transpeptidase catalyzes reactions that course the cell wall. The enzyme forms a complex with penicillin 1000, and the carbonyl group reacts with a serine hydroxyl group contained in the agile site of the enzyme. The kickoff step of the reaction is germination of a tetrahedral intermediate.

The tetrahedral intermediate then collapses to give an acyl enzyme, which hydrolyzes to requite a penicillinic acid.

Most amides are ineffective acylating agents. Still, the iv-membered band of a β-lactam is strained. Relief of strain provides the driving strength for its reaction with nucleophiles.

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Progress in Heterocyclic Chemistry

Benito Alcaide , Pedro Almendros , in Progress in Heterocyclic Chemistry, 2009

4.iv Fused and spirocyclic β-lactams

The chemistry of cephalosporins and penicillins has been reviewed < 08CHEC-III111; 08CHEC-III173>. The combative interactions between the flavonoids hesperetin and naringenin and β-lactam antibiotics against Staphylococcus aureus take been described <08MI145>. The quantitative memory-action relationships (QRAR) model of β-lactam antibiotics has been studied <08MI2>. The increased antibacterial activity of β-lactam heterodimers in comparison with their monomeric components has been reported <08JAN595>. The reaction of Schiff bases derived from 3-cyano-2,4-diamino thiophene with chloroacetyl chloride afforded spiro-β-lactams <08PS1679>. The heterocyclizative cross-coupling between 2-azetidinone-tethered allenols and a-allenic acetates gave β-lactam-dihydrofuran hybrids 27 in skilful yields <08CAJ1140>. New three-heterocycle substituted 1,iii-thiazolidine-derived 4-spiro-β-lactams with a relative trans-configuration take been stereoselectively synthesised by means of a Staudinger ketene-imine reaction <08TA554>. Oxacyclopropane formation gives the highly strained oxiranyl-β-lactam 28, possessing a spirocyclic construction by treatment of a three-[bromo(nitro)methyl] 3-hydroxy-β-lactam with bases <08OBC1635>. A novel Pd(Ii)-catalyzed C-H lactamization reaction, including the formation of spiro-β-lactams has been achieved <08JA14058>.

Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C 29 which has a spirocyclic β-lactam unit, have been described <08CC3121>. The isolation, structural elucidation and biological characterization of phyllostictine A, a new phytotoxic oxatricyclic β-lactam 30, produced in liquid civilization by P. cirsii, have been described <08T1612>. Various glutaryl acylase mutants have been evaluated to ameliorate the hydrolysis of cephalosporin C 31 in the absence of hydrogen peroxide <08ASC343>. A thermal decarbonylation of penam β-lactams has been developed <08JOC3024>. Mechanisms for the hydrolysis of nitrocefin and penicillin M have been proposed <08JA14207; 08JA15842>. β-Lactams have been examined every bit selective chemic probes for the in vivo labeling of bacterial enzymes involved in prison cell wall biosynthesis, antibody resistance, and virulence <08JA13400>. A study of the biosensing process involving fluorophore-labeled β-lactamase as a biosensor for β-lactam antibiotics has been carried out <08JA6351>. The resolution of racemic 2-chlorophenyl glycine with immobilized penicillin G acylase has been achieved <08TA2363>.

An approach for synthesizing a series of 2-sulfide carbapenems has been developed using two successive Cu(I)-catalyzed cross-couplings in a single pot <08OL2737>. Two different stereocontrolled accesses to new 4-hydroxypipecolic acid analogues 32 with a bicyclic β-lactam structure have been developed past using intramolecular reductive amination or allenic hydroamination reactions in ii-azetidinone-tethered azides <08JOC1635>. A variety of β-lactams bearing protected polar substituents was generated from chlorosulfonyl isocyanate (CSI)-derived building blocks <08OL5317>. ane-Allyl-substituted 4-(ii-bromo-1,1-dimethylethyl)azetidin-two-ones take been transformed into bicyclic β-lactams through radical cyclization past means of n-tributyltin hydride and AIBN in toluene with excellent diastereocontrol <08JOC1422>. It has been reported that chlorosulfonyl isocyanate addition to (−)- and (+)-apopinene furnished monoterpene-fused β-lactams in highly regio- and stereospecific reactions <08TA2296>. A convenient arroyo to novel selenium-β-lactams such as iii-selena-1-dethiacephems 33 involved a regioselective iodocyclization <08OL3319>. The chemoselective cycloetherification reaction of enallenols under iron-catalyzed conditions resulted in the grooming of bicyclic β-lactams 34 <08CEJ7756>. The stereoselective synthesis of carbapenams via Kinugasa reaction involved cyclic nitrones derived from malic and tartaric acid <08JOC7402>. A iii-pace procedure involving imine formation/Staudinger reaction/Pauson-Khand cycloaddition enabled the preparation of fused-tricyclic azetidinones from the reaction of N-tosyl-North-allyl ketene with complexed acetals derived from propargylic aldehydes <08JOC8469>. A CeCl3·7H2O/NaI-promoted synthetic protocol for strained tricyclic β-lactams 35 has been developed from hydrazines <08TL5553>. The reaction of 3-arylisoxazoles with LDA in THF at 0 °C afforded syn-ii,6-diaryl-three,7-diazatricyclo[4.2.0.0two,5]octan-4,viii-diones (bis-azetidinones), via stereoselective dimerization of an azetidinone anion intermediate <08T11198>. A ring closing metathesis approach to N1-C3 bridged macrocyclic β-lactams has been developed <08T9592>. The synthesis and structural characterization of β-lactam condensed three-thiaquinolines have been achieved <08T1002>. a,β-Unsaturated aldehydes, including 3-alkyl derivatives, undergo Due north-heterocyclic carbene (NHC)-catalyzed annulations with North-sulfonyl ketimines to provide bicyclic β-lactams 36 with outstanding diastereo- and enantioselectivity <08JA418>.

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A critical review of the 2004 literature preceded by two chapters on electric current heterocyclic topics

Benito Alcaide , Pedro Almendros , in Progress in Heterocyclic Chemistry, 2005

4.four FUSED POLYCYCLIC β-LACTAMS

The development of a cephalosporin-based dual-release prodrug < 04JOC7965> as well every bit a study on penicillins as β-lactamase-dependent prodrugs take been described <04CC2332>. The X-ray crystal structure of an acylated β-lactam sensor domain has been reported <04JA13945>. The reaction mechanism of hydrolysis of a mutual β-lactam substrate (cefotaxime) past monozinc β-lactamase has been investigated <04JA12661>. The unusual bifunctional catalysis of epimerisation and desaturation by carbapenem synthase has been analyzed <04JA9932>. The Mössbauer spectra of isopenicillin N synthase has been studied <04JA9494>. The inhibition of a bacterial DD-peptidase by the newly prepared peptidoglycan-mimetic β-lactam 39 has been described <04JA8122>. A sensitive and reagentless biosensor for β-lactam antibiotics such equally cefuroxime 40 has been synthetic from a modified class A β-lactamase <04JA4074>. Two penicillin derivatives, the active penamecillin and the inactive penamecillin-1β-sulfoxide, were used to study the relationship between their accuse density and their activity <04CEJ2977>. Mixed ab initio quantum mechanical/molecular mechanical calculations have been used to study the hydrolysis of the acyl-enzyme intermediate formed between cephalothin and a class C β-lactamase <04JA7652>. The kinetics and mechanism of hydrolysis of N-acyloxymethyl derivatives of azetidin-2-ane have been studied <04JOC3359>. A kinetic analysis has been reported of the hydroxyaminolysis of β-lactam antibiotics <04OBC651>.

A method has been established to synthesize 6-methylidene penem compounds, which involves an aldol-type condensation on six-bromopenem with aldehydes <04JOC5850>. S-Alkyl dithioformates, generated by a cycloreversion process, react as one,3-dipolarophiles with β-lactam-based azomethine ylides to provide, afterwards elimination of MeSH, C2-unsubstituted penems 41 <04OL2781>. Information technology has been reported that selenapenams and selenacephems can be prepared by nucleophilic and radical chemistry involving benzyl selenides <04OBC2612>. The synthesis of bicyclic β-lactam 42 has been accomplished by radical cyclization <04OL4053>. Two polymorphs of trans-13-azabicyclo[10.2.0]tetradecan-14-one display a unique example of isostructurality, differing only in the orientation of a given hydrogen bond with respect to the β-lactam bond<04CC2114>.

The formation of β-lactam derivatives 43 through the reaction of dibenzoylacetylene and aryl isocyanates in the presence of trivalent phosphorus nucleophiles has been documented <04S237>. It has been reported that the carbamoyl radical cyclization reaction through dithiocarbamate grouping transfer is a useful tool for the preparation of β-lactams such as 44 <04AG(E)3445>. Via the Ugi 4-centre three-component reaction, bicyclic cis-ii-azetidinone derivatives take been synthesized from circadian β-amino acids <04MI215>, and a synthesis of strained band-fused β-lactams 45 by Ugi reaction of β-keto acids in aqueous solution has been described <04SL1425>. The synthesis and rearrangement of North-organyloxy β-lactams 46 derived from a (4+2)/(iii+2) sequential cycloaddition reaction involving enol ethers and nitro alkenes has been reported <04EJO4397>. Using ring closing metathesis as the key functioning, a rapid admission to β-lactams 47 fused to a sultam moiety of variable ring size has been developed <04TL3589><04S1696>.

The synthesis of 4/5/6, 4/6/6 and iv/7/6 tri- and tetracyclic β-lactams 48 has been carried out via i-pot enyne metathesis and Diels–Alder reactions <04S2665><04EJO4840>. The synthesis of unprecedented inner-outer-ring 2-[tert-butyldimethylsilyloxy]dienes with a carbacepham structure in optically pure form and their totally π-facial endo selective Diels–Alder reactions to structurally novel polycyclic β-lactams 49 has been reported <04TL7255>.

A stereoselective and substrate-controlled synthesis of polycyclic β-lactams 50 from a d-glucose-derived chiral template via intramolecular radical cyclization has been described <04S2965><04SL1249>. The [two+2]-cycloaddition of chlorosulfonyl isocyanate to polymerbound vinyl ethers followed past intramolecular alkylation of the β-lactam nitrogen led to the germination of mixtures of the respective diastereomeric oxacephams or clavams with a depression stereoselectivity. In the case of Merrifield and MPP resins, the β-lactams were accompanied by the respective oxetanes or oxiranes <04EJO4177>. Novel tricyclic scaffolds 51 that incorporate a β-lactam ring fused to the d bond of a 1,4-benzodiazepine vii-membered ring take been synthesized in a process that constitutes one of the few examples of Staudinger-type reactions involving ketimines described so far. In addition, the creation of an asymmetric quaternary center has been achieved <04EJO535>. The [2+2] Staudinger cycloaddition betwixt the C=N double bond of 2,3-dihydrobenzoxazepines and a serial of acetyl chlorides gave azetidino[four,1-d][1,4]benzoxazepines <04TA2555>. Racemic every bit well as optically pure fused tricyclic β-lactams accept been regio- and stereoselectively prepared via intramolecular nitrile oxide-alkene cycloaddition reactions of 2-azetidinonetethered alkenyl oximes or nitro alkanes. The process is more efficient when the nitrile oxide moiety is separated by a methylenic grouping, rather than being directly linked to the C-4 position of the four-membered band <04MI137>.

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Four-membered Heterocycles, and all Fused Systems with a Four-membered Heterocyclic Ring

Ermal Ismalaj , Wim De Borggraeve , in Comprehensive Heterocyclic Chemistry IV, 2022

two.02.5.9 Rearrangement reactions involving the penam skeleton

The transformations of penicillins into cephalosporins via ring expansion is of huge importance every bit far every bit information technology allows straight access to another class of β-lactam antibiotics. The reaction has been already reported in CHEC-II (Section one.20.v.8) and CHEC-Iii (Section two.03.5.nine).

Thermal rearrangement of penicillin sulfoxide 58 gives an equilibrium with sulfenic acid 59 via the opening of the thiazolidine band which, upon further treatment with a Brønsted acid, leads to cephalosporins 61, nigh probably via episulfonium intermediate 60 (Scheme 19).

Scheme 19

Scheme 19. Synthesis of cephalosporins 61 starting from penicillin via thiazolidine ring opening.

 Reproduced from Marchand-Brynaert, J.; Brulé, C. In Comprehensive Heterocyclic Chemistry 3, Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; pp 173–237.

A few years ago, this strategy was applied in the synthesis of silyl-protected Cephalosporin 1000 from Penicillin Thousand in a 90% yield and with a purity college than 98% (Scheme 20). 108

Scheme 20

Scheme 20. Synthesis of Cephalosporin 1000 starting from Penicillin Chiliad.

Calixarene-supported penam sulfoxides 64 underwent band expansion yielding calixcephem 65 (Scheme 21). After silyl ester germination using 1,3-bis(trimethylsilyl)urea, the reaction proceeds via pyridine-HBr mediated ring opening and closing, followed by the germination of an episulfonium intermediate and band rearrangement. Chemical compound 65 has been obtained subsequently bicarbonate-mediated hydrolysis of the silyl ester followed by protonation with H2SO4. 146

Scheme 21

Scheme 21. Synthesis of calixcephems 65 starting from calixpenicillins 64.

Rearrangements involving β-lactam ring opening followed by a cyclization have as well been reported recently (Scheme 22). vi-APA 66 in sodium bicarbonate solution reacts with COtwo and the carbamate formed gives rise to 8-hydroxypenillic acid 67. 142

Scheme 22

Scheme 22. Synthesis of eight-hydroxypenillic acrid from 6-APA.

 Reproduced from Liu, C. J.; Dutta, D.; Mitscher, L. Chin. Chem. Lett. 2015, 26(i), 113–117.

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An Industrial Perspective on Total Synthesis; Penem Antibacterial CP-70,429

Robert A. Volkmann , Brian T. O'Neill , in Strategies and Tactics in Organic Synthesis, 1991

I Introduction: Discovery of Penem Antibacterial CP-65,207 (7)

Penicillin (ane ) and cephalosporin ( two) antibiotics take established an unparalleled record of safety and reliability in the treatment of infectious disease during the final half of this century. A issue of widespread clinical acceptance of these β-lactam antibiotics has been an increase in resistance by target bacteria thus compromising the efficacy of many of these drugs. Bacterial resistance, coupled with the need to widen the spectrum of these agents, has fueled the search for novel therapeutics from both constructed and natural sources. The discovery of penems and carbapenems, ii new families of β-lactam antibacterials, was an outgrowth of these efforts.

In 1976, the Woodward/Ciba group prepared the starting time penem (3) 1 , a structural hybrid of penicillins and cephalosporins. The antibacterial activity of these novel 6-acylaminopenems was disappointing; however, the Merck discovery of the broad-spectrum carbapenem, thienamycin (4) 2 , from fermentation sources, demonstrated that novel β-lactams, devoid of fundamental penicillin and cephalosporin structural features, would be capable of potent antibacterial action. The structural relationship between carbapenems and penems suggested a further refinement of the penem structural class in the class of 2-thioalkylpenems 5 which displayed an impressive antibacterial

contour. The commercial implications of this discovery were obvious. As a result, Mike Kellogg, Ernie Hamanaka, Bob Rosati, and coworkers at Pfizer initiated a synthetic programme aimed at the discovery of strong penem antibacterials. By no means were they alone in their chemical efforts as an explosion in β-lactam research occurred in other laboratories at the same time every bit a result of the carbapenem/penem discoveries.

The seminal contributions by individuals in early penem/carbapenem research are too numerous to mention at this juncture. Certainly synthetic methodology developed by the Woodward/Ciba group and also at Schering, Merck, Sankyo, Bristol-Myers, Farmitalia Carlo Erba, and other companies factored into our drug discovery efforts. 3 In 1983 Dave Johnson and Bob Martingano, working with Ernie Hamanaka, prepared a series of 2-thioalkylpenems past treatment of known enantiomerically pure intermediate six iv with a series of racemic heterocyclic thiolates. They were convinced that polar substituents appended to the carbapenem/penem skeleton (such as the β-aminoethylsulfide moiety in thienamycin) were responsible for the breadth (gram negative activity) of spectrum and balance of potent antibacterial activity of these compounds. The most notable substance generated from their synthetic efforts was CP-65,207 (7) 5 , a diastereomeric mixture of cis-thiophanesulfoxide-containing penems with a remarkably well-balanced antimicrobial spectrum (Eq. 1). Considering of its impressive biological credentials, CP-65,207 (7) was nominated in 1984 equally a candidate for clinical development at Pfizer.

(1)

It was well-nigh this time when the project team was confronted by the sobering realities of pharmaceutical development. Initial cost estimates for the production of CP-65,207 (7) and other members of the series were astronomical. Nosotros were not alone in the realization that the commercial potential of the penem/carbapenem class would depend on the development of highly efficient syntheses. Merck had already responded aggressively to the challenge of drug evolution past uncovering a more stable analog of thienamycin, imipenem, and developing a commerical process for its synthesis. Our course was also clearly defined and nosotros began to evaluate, in earnest, possible synthetic routes to CP-65,207 (7).

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