Azetidinone antibiotics. XII. Chemical transformations of penicillins and cephalosporins. Mechanism and stereochemistry of the interconversions of penam and cepham systems

Kukolja, Stjepan; Lammert, S. R.; Gleissner, M. R.; ELLIS, A. I.

doi:10.1021/ja00844a045

Cited by 27 publications

(12 citation statements)

References 5 publications

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“…Subsequently, a 1,3-trans-ring attack of the S-atom at C(3) takes place, the C1-atom being released and an episulfonium ion 9 formed. Contraction from a six-to five-membered ring via an episulfonium intermediate was previously observed in the synthetic interconversion of cepham and penam systems [32]. Baertschi et al [I51 previously considered the formation of this type of intermediate in the degradation of cefaclor (1) in an acidic medium.…”

Section: Co2-mentioning

confidence: 95%

The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

Vilanova

Donoso

Muñoz

et al. 1996

Helvetica Chimica Acta

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The degradation of cefaclor (l), an oral cephalosporin antibiotic, was studied at 37O in a neutral aqueous medium by HPLC and 'H-NMR. Under these conditions, 1 underwent intramolecular aminolysis by the 7-sidechain NH, group on the 8-lactam moiety to give a piperazine-2,s-dione. The most prominent peak in the HPLC profile of a degradation solution from 1 was isolated by prep. HPLC. Mechanistically, the formation of this degradation product cis-11 from 1 involves the contraction from a six-membered cephem ring to a live-membered ring, which presumably takes place via a common episulfonium ion intermediate 9 (see Scheme). Loss of the C1-atom from 3-chloro-3-cephem is a general reaction subsequent to b-lactam ring opening.

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Section: Co2-mentioning

confidence: 95%

The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

Vilanova

Donoso

Muñoz

et al. 1996

Helvetica Chimica Acta

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“…The structure is based on elemental analysis and spectral data obtained for 5a and for its methyl and benzyl ester (5b and 5c). The NMR spectra showed a coupling constant of 14.5 Hz for the geminal CH2, which is a typical value for a halocepham structure14,15) (the 2J value for an isomeric halogenopenam is about 12 Hz14,15)) The assumed /3-bromo configuration is based on mechanistic considerations discussed by KUKOLJA et al 16) and the reaction is supposed to be similar to that described by KAMIYA et a1.17) These authors obtained a mixture of a 2-chloromethylpenam and 3c upon treatment of 2c with pyridine-HCI and pyridine in tetrachloroethane. The cepham structure proposed for 5a is not in disagreement with the experiment described by KAMIYA et al, since it is known16, 17) that 2-bromopenams easily rearrange into the more stable 3-bromocephams.…”

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confidence: 89%

Preparation of .DELTA.3-7.ALPHA.-phenylacetamidodesacetoxycephalosporanic acid.

et al. 1979

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J3-7a-Phenylacetamidodesacetoxycephalos poranic acid was prepared by ring expansion of 6-epi-benzylpenicillin-S-sulfoxide, using N,O-bis(trimethylsilyl)acetamide (BSA) as silylating and dehydrating agent and a-picoline/a-picoline hydrobromide as catalyst. In some experiments 7a-phenylacetamido-3/9-bromo-3a-methylcepham-4a-carboxylic acid was obtained as a side product. 7-Epimers in the desacetoxycephalosporanic series were also prepared by base-catalyzed epimerization of the benzyl 7 fl-(p-nitrobenzylideneimino)desacetoxycephalosporanate and of the S-sulfoxide of natural methyl 6-phenylacetamidodesacetoxycephalosporanate. In both reactions 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) was used as epimerization catalyst.The present report deals with the preparation of J3-7a-phenylacetamidodesacetoxycephalosporanic acid (Ia), which was needed in the course of a study of the substrate specificity of Escherichia coli penicillin acylase1). 7-Epimers in the cephalosporanic acid series have been prepared by acid-catalysed ring expansion of 6-epi-penicillins2,3), by epimerization of cephalosporanic acid derivatives with a natural configuration4~6), and also by total synthesis7). Only the first two methods are investigated in this study in view of the preparation of Ia. Ring expansion will be considered first.The conversion of penicillin sulfoxides (2) into A3-desacetoxycephalosporins (3) by an acid-catalysed ring expansion was originally reported by MORIN et al.8) Reviews on the chemical interconversion of 13-lactam antibiotics were published by COOPER et al.9,10) The ring expansion was also described for 6-epi-penicillins2,3), as mentioned earlier. Since the rearrangement of a free acid of penicillin sulfoxide into desacetoxycephalosporanic acid proceeds with extensive decarboxylatione', the reaction is limited to esters. Thus procedures, described upto 1974, did not permit the preparation of a free acid or an alkali salt of "3-desacetoxycephalosporins in a single step. In 1975 DE KONING et al.11), reported a procedure in which the rearrangement is carried out on the free acid of benzylpenicillin sulfoxide (2a), using N,O-bis(trimethylsilyl)acetamide (BSA) as silylating-and dehydrating agent and a-picoline and its hydrobromide as catalyst. By this procedure L3-7a-phenylacetamidodesacetoxycephalosporanic acid (3a) is obtained in a single step in high yield (78 %). Another one-step procedure has been described by MIKOLAJCZYK et al.12) The procedure described by DE KONING et al. was applied for the preparation of Ia. It should be mentioned that the starting material for this compound, the free acid of 6-epi-benzylpenicillin-S-sulfoxide13) (4a), is a monohydrate (as shown by NMR). Therefore it is necessary to increase the ratio BSApenicillin from ~3: 1 (as described in the original method) to ~4: 1. It was also observed that the ring expansion of 4a is faster than that of the epimer with natural configuration 2a. After heating for 60-90 minutes at 100°C no starting sulfoxide (4a) was found to be present in the reaction mixture...

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“…One of us [7] has suggested that biosynthesis of penicillin N (S), deacetoxycephalosporin C(9), and closely related substances could possibly be explained as proceeding via a common thiiranium ion (10) (Ra = (2-amino-6-adipyl)amino, R = H; see Scheme). The formation of the final products most likely depends upon conditions in fermentation processes.…”

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confidence: 99%

“…Some other peaks indicated that other unidentified species had been formed. When a fresh solution of the P-sulfoxide 4 was prepared, it was found that the C(2) resonance disappeared within [5][6][7][8] hours. These changes suggest that in the case of the P-sulfoxide 4 there is a rapid tautomeric exchange of the C(2) protons for deuterium.…”

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confidence: 99%

High performance liquid chromatography (HPLC) of natural products part VI. Sulfoxides of penicillin N and cephalosporin c and their role in biosynthesis of β‐lactam antibiotics

Kukolja

Miller

Duckworth

et al. 1984

Helvetica Chimica Acta

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SummaryPure penicillin N a-sulfoxide (1) and penicillin N 8-sulfoxide (2) were obtained by HPLC and tested as substrates for deacetoxycephalosporin C synthetase (DXCS). Neither one of the sulfoxides was utilized under conditions of conversion of penicillin N (8) to deacetoxycephalosporin C (9). The cephalosporin C a-and 8-sulfoxides (3 and 4, resp.) were also prepared. Relative stabilities of the sulfoxidles 3 and 4 are discussed by interpretation of the I3C-NMR spectra.In a series of publications from our laboratories we have shown a convenient way to follow the isolation and identification of different metabolites from the fermentation broth using HPLC [2]. We have applied a similar technique lo the study of cell-free biosynthesis of p-lactam antibiotics [ 11.A penicillin N sulfoxide had been first suggested by Abraham & Newton (1965) [3] and later by Troonen et a/. (1976) [4] as a possible intermediate in the conversion of penicillin N (8) to deacetoxycephalosporin C (9). These assumptions were made on the basis of analogy with the nonbiological conversion of penicillin to cephalosporins first described by Morin et al. (1963) [5]. Baldwin et al. (1980) [6] mentioned, however, that there was no evidence of cephalosporin formation when 8-sulfoxide 2 or 5 of penicillin N and isopenicillin N, respectively, were added to protoplast lysates prepared from Cephalosporium unlike in the case where synthetic samples of (~-2-amino-6-adipyl)-~-cysteinyl-D-valine (6), isopenicillin N (7), or penicillin N (8) were added as precursors of the formation of deacetoxycephalosporin C (9).One of us [7] has suggested that biosynthesis of penicillin N (S), deacetoxycephalosporin C(9), and closely related substances could possibly be explained as proceeding I ) For part V, see [I].

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Azetidinone antibiotics. XII. Chemical transformations of penicillins and cephalosporins. Mechanism and stereochemistry of the interconversions of penam and cepham systems

Cited by 27 publications

References 5 publications

The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

Preparation of .DELTA.3-7.ALPHA.-phenylacetamidodesacetoxycephalosporanic acid.

High performance liquid chromatography (HPLC) of natural products part VI. Sulfoxides of penicillin N and cephalosporin c and their role in biosynthesis of β‐lactam antibiotics

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