Novel conversion of a 3-(1-hydroxyethyl)azetidinone to a 3-(hydroxymethyl)azetidinone: a synthesis of 6-(hydroxymethyl)-1.beta.-methylcarbapenem

Ruediger, E. H.; Solomon, Carola

doi:10.1021/jo00009a048

Cited by 13 publications

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“…Treatment with TFA, followed by β-lactam cyclization, 15 gave 13. Standard allyl ester deprotection conditions 16 (i.e., Pd[PPh 3 ] 4 , potassium 2-ethylhexanoate) yielded 2, but with large amounts of contaminating/side products that could not be removed without causing further product decomposition. Finally, utilizing the Pd[PPh 3 ] 4 /p-toluenesulfinate sodium salt deprotection protocol, 17 the labile 2 was obtained with minimal amounts of decomposition.…”

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“…Recognizing the utility of removing allyl esters in pH sensitive substrates by Pd[PPh 3 ] 4 catalysts, we turned our attention to the deprotection of (3 S ,5 S )-carbapenam allyl ester 13 (Scheme ) as a test case prior to the synthesis of the (3 S ,5 R )-carbapenam system (Scheme ). An added advantage in this instance is that the allyl group acts as a two-atom spacer, potentially allowing better interaction with the Pd catalyst during deprotection, compared to the failed hydrogenolysis attempts.…”

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Synthesis of (3S,5R)-Carbapenam-3-carboxylic Acid and Its Role in Carbapenem Biosynthesis and the Stereoinversion Problem

Stapon

Townsend

2003

J. Am. Chem. Soc.

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(5R)-Carbapenem-3-carboxylic acid is the simplest structurally among the naturally occurring carbapenem beta-lactam antibiotics. It is the produced from (3S,5S)-carbapenam-3-carboxylic acid utilizing a remarkable stereoinversion/desaturation process by CarC (carbapenem synthase), an alpha-ketoglutarate dependent non-heme iron oxygenase. In this communication, we demonstrate for the first time that the epimeric (3S,5R)-carbapenam-3-carboxylic acid is an intermediate in the overall catalytic cycle to the carbapenem antibiotic. The role of alpha-ketoglutarate in the stereoinversion and desaturation processes is also examined.

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Synthesis of (3S,5R)-Carbapenam-3-carboxylic Acid and Its Role in Carbapenem Biosynthesis and the Stereoinversion Problem

Stapon

Townsend

2003

J. Am. Chem. Soc.

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β‐Lactam Antibiotics

Andreotti

Biondi

Modugno

2003

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews the history of β‐lactams from the discovery of penicillin in 1928 to the more recently studied and the current trends in the field. The most relevant aspects related to the mechanism of action of β‐lactams are covered, and the various mechanisms of resistance to currently available β‐lactams that bacteria have adopted since the introduction of penicillin are described. A classification of β‐lactamases and their relevance in clinics is also provided. Applications of β‐lactams both in the hospital and in the community are reported, with particular attention to their pharmacokinetic properties, related side effects, and their therapeutic indications. The history and discovery of β‐lactams are described and all major classes are covered: penicillins, cephalosporins, oxacephems, carbacephems, penems, monobactams and nocardicins, carbapenems and trinems, classical (e.g., clavulanic acid, sulbactam, tazobactam), and the more recently disclosed β‐lactamase inhibitors. Several aspects related to the most recent developments in β‐lactams are also covered: new molecules active against difficult Gram‐positive strains or endowed with an antibacterial broad spectrum of action; potent orally active β‐lactams; injectable β‐lactams; and β‐lactamase inhibitors. The chapter concludes with a continuing analysis of the industry‐driven trends and the most recent new application of β‐lactams as inhibitors of protein export in bacteria. Finally, a few very interesting Web addresses and a comprehensive reference list are also provided.

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β‐Lactam Antibiotics

Testero

Fisher

Mobashery

2010

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β‐lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β‐lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β‐lactam resistance, alterations to the molecular targets of the β‐lactams (the penicillin binding proteins) and the use of enzymes (the β‐lactamases) capable of the hydrolytic deactivation of the β‐lactams are paramount. This review traces the historical development of β‐lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β‐lactams leading to the discovery of new generation β‐lactam antibacterials effective against the Gram‐negative and ‐positive bacterial pathogens of current medical concern.

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Novel conversion of a 3-(1-hydroxyethyl)azetidinone to a 3-(hydroxymethyl)azetidinone: a synthesis of 6-(hydroxymethyl)-1.beta.-methylcarbapenem

Cited by 13 publications

References 3 publications

Synthesis of (3S,5R)-Carbapenam-3-carboxylic Acid and Its Role in Carbapenem Biosynthesis and the Stereoinversion Problem

Synthesis of (3S,5R)-Carbapenam-3-carboxylic Acid and Its Role in Carbapenem Biosynthesis and the Stereoinversion Problem

β‐Lactam Antibiotics

β‐Lactam Antibiotics

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