Expeditious Synthesis of 4-(<i>tert</i>-Butylcarbonyl)-7α-methoxy-3-methyl-Δ<sup>3</sup>-cephem 1,1-Dioxide. Convenient Access to 7-Substituted Analogues

Alpegiani, Marco; Bissolino, P.; D'Anello, Matteo; Palladino, Massimiliano; Perrone, Ettore

doi:10.1055/s-1998-1621

Cited by 4 publications

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“…Our investigation 3 has resulted in the disclosure of original 1,1dioxocephem 4-ketones 4 and tricyclic cephem sulfones. 5 As their synthesis mostly relies on the exploitation of the key-intermediates 1 and 2, we sought for improved methods of preparing both synthons: herein and in the accompanying paper 6 we report our findings on this subject. Scheme 1 outlines the retrosynthetic pathway according to which we had previously obtained cephem 1 starting from 7α-methoxy-3deacetoxycephalosporanic acid 3.…”

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Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones

Alpegiani¹,

Bissolino²,

D'Anello³

et al. 1998

Synlett

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1,1-Dioxo-7α-methoxy-3-methyl-∆ 3 -cephem-4-yl phenyl ketone, a valuable precursor of potent HLE inhibitors, was obtained in an efficient way starting from 7α-methoxy-3-methyl-∆ 3 -cephem-4-carboxylic acid. By employing the same methodology a variety of 1,1-dioxocephem-4-yl aryl ketones were prepared.Until a decade ago cephem derivatives had long been known only for their antibacterial properties attained through inhibition of bacterial peptidases. 1 During the last decade the capability of modified cephalosporins to inhibit mammalian serine proteinases, and in particular human leukocyte elastase (HLE), has been ascertained. 2 The prospective use of cephems as antiinflammatory drugs in human therapy has fostered renewed efforts to explore the cephem field both from a chemical and a biological point of view.Our investigation 3 has resulted in the disclosure of original 1,1-dioxocephem 4-ketones 4 and tricyclic cephem sulfones. 5 As their synthesis mostly relies on the exploitation of the key-intermediates 1 and 2, we sought for improved methods of preparing both synthons: herein and in the accompanying paper 6 we report our findings on this subject.Scheme 1 outlines the retrosynthetic pathway according to which we had previously obtained cephem 1 starting from 7α-methoxy-3-deacetoxycephalosporanic acid 3. 7 Carbon-carbon bond formation was the critical step, and acid chloride 4, uneventfully obtained from acid 3, was converted into phenyl ketone 5 upon treatment with phenylmagnesium chloride/copper(I) iodide. 4 Scheme 1In developing an alternative synthetic plan we were guided by two main considerations elaborated on the basis of other researchers' and our own experience in the field of cephem chemistry. Firstly, cephem esters had been reported to undergo regioselective acylation at C-4. 8 Secondly we had observed the easy decarboxylation of 4-alkyl-4-carboxy-∆ 2 -cephem sulfones to provide 1,1-dioxo-4-alkyl-∆ 3 -cephems. 9 Both these features turned out to be the keystones of an efficient synthetic pathway, according to which the targeted 4-benzoyl cephem 1 was obtained in five steps from the cheap and commercially available 7β-amino-3-deacetoxycephalosporanic acid (7-ADCA) (Scheme 2).The methoxy-deamination reaction of 7-ADCA to provide 7α-methoxy-3-deacetoxycephalosporanic acid 3 7 was optimised in terms of safety and reproducibility by substituting methanesulfonic acid for perchloric acid in the diazotation of 7-ADCA; crude acid 3 was then protected 10 with p-methoxybenzyl chloride (NaBr, NaHCO 3 , DMF) affording ester 6 11 in satisfactory yield. Upon treatment of 6 with LDA (1.1 mol equiv, THF, -70 °C) and then with benzoyl chloride (1.5 mol equiv, -70 °C) the C-4 acylated ∆ 2 -cephem 7 was produced as a single diastereomer in about 75% yield. It is noteworthy that the delocalized carbanionic species, generated by removal of a cephem C-2 proton, undergoes Scheme 2Downloaded by: University of Liverpool. Copyrighted material. LETTERS SYNLETTacylation with remarkable regio-and stereoselectivity. On mechanistic g...

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confidence: 99%

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones

Alpegiani¹,

Bissolino²,

D'Anello³

et al. 1998

Synlett

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ChemInform Abstract: Expeditious Synthesis of 4‐(tert‐Butylcarbonyl) ‐7α‐methoxy‐3‐methyl‐Δ³‐cephem 1,1‐Dioxide. Convenient Access to 7‐Substituted Analogues.

et al. 1998

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Expeditious Synthesis of 4-(tert-Butylcarbonyl) -7α-methoxy-3methyl-∆ 3 -cephem 1,1-Dioxide. Convenient Access to 7-Substituted Analogues.-An efficient and practical route for the synthesis of the cephem ketone (III), a key intermediate in the preparation of potent inhibitors of mammalian serine proteinases, is described. The diazo compound from (III) allows access to a variety of further cephems substituted at position 7. -(ALPEGIANI, M.; BISSOLINO, P.; D'ANELLO, M.; PALLADINO, M.; PERRONE, E.; Synlett (1998) 3, 322-324; Pharmacia & Upjohn SpA, I-20014 Nerviano, Milano, Italy; EN)

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Comprehensive Organic Functional Group Transformations II

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Expeditious Synthesis of 4-(tert-Butylcarbonyl)-7α-methoxy-3-methyl-Δ³-cephem 1,1-Dioxide. Convenient Access to 7-Substituted Analogues

Abstract: A practical and efficient route leading to the synthesis of 4-

Cited by 4 publications

References 4 publications

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones

ChemInform Abstract: Expeditious Synthesis of 4‐(tert‐Butylcarbonyl) ‐7α‐methoxy‐3‐methyl‐Δ³‐cephem 1,1‐Dioxide. Convenient Access to 7‐Substituted Analogues.

Functions Incorporating a Halogen and a Chalcogen

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Expeditious Synthesis of 4-(tert-Butylcarbonyl)-7α-methoxy-3-methyl-Δ3-cephem 1,1-Dioxide. Convenient Access to 7-Substituted Analogues

Abstract: A practical and efficient route leading to the synthesis of 4-

Cited by 4 publications

References 4 publications

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ3-cephem-4-yl Aryl Ketones

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ3-cephem-4-yl Aryl Ketones

ChemInform Abstract: Expeditious Synthesis of 4‐(tert‐Butylcarbonyl) ‐7α‐methoxy‐3‐methyl‐Δ3‐cephem 1,1‐Dioxide. Convenient Access to 7‐Substituted Analogues.

Functions Incorporating a Halogen and a Chalcogen

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Expeditious Synthesis of 4-(tert-Butylcarbonyl)-7α-methoxy-3-methyl-Δ³-cephem 1,1-Dioxide. Convenient Access to 7-Substituted Analogues

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones

ChemInform Abstract: Expeditious Synthesis of 4‐(tert‐Butylcarbonyl) ‐7α‐methoxy‐3‐methyl‐Δ³‐cephem 1,1‐Dioxide. Convenient Access to 7‐Substituted Analogues.