112240-59-2Relevant academic research and scientific papers
A straightforward synthesis of proclavaminic acid, a biosynthetic precursor of clavulanic acid
Di Giovanni, Maria Cristina,Misiti, Domenico,Villani, Claudio,Zappia, Giovanni
, p. 2277 - 2286 (1996)
A stereocontrolled synthesis of (2S,3R)-5-amino-3-hydroxy-2-(2-oxoazetin-1-yl) pentanoic acid, proclavaminic acid 3, has been achieved via the homochiral 4,5-disubstituted oxazolidin-2-one 4.
Synthesis of the Novel Monocyclic β-Lactam Proclavaminic Acid
Baggaley, Keith H.,Sime, John T.,Nicholson, Neville H.,Elson, Stephen W.,Gillett, Janet,et al.
, p. 1738 - 1739 (1987)
Proclavaminic acid has been chemically synthesized and one pure enantiomer separated which was shown to possess identical physicochemical and biochemical properties to the natural material isolated from Streptomyces clavuligerus.
Product-substrate engineering by bacteria: Studies on clavaminate synthase, a trifunctional dioxygenase
Lloyd, Matthew D.,Merritt, Kirsten D.,Lee, Victor,Sewell, Timothy J.,Wha-Son, Byeng,Baldwin, Jack E.,Schofield, Christopher J.,Elson, Steve W.,Baggaley, Keith H.,Nicholson, Neville H.
, p. 10201 - 10220 (1999)
Evidence is presented that clavaminate synthase (CS) catalyses three oxidative reactions in the clavulanic acid biosynthetic pathway. The first CS catalysed step (hydroxylation) is separated from the latter two (oxidative cyclisation and desaturation) by the action of a hydrolytic enzyme, proclavaminate amidinohydrolase, which modifies (or 'mutates') the sidechain of the product of the first reaction thereby converting it into a substrate for the second CS catalysed reaction.
β-Secondary Kinetic Isotope Effects in the Clavaminate Synthase-Catalyzed Oxidative Cyclization of Proclavaminic Acid and in Related Azetidinone Model Reactions
Iwata-Reuyl, Dirk,Basak, Amit,Townsend, Craig A.
, p. 11356 - 11368 (2007/10/03)
Clavaminate synthase is an Fe(II)/α-ketoglutarate-dependent oxygenase that catalyzes three mechanistically distinct reactions in the course of clavulanic acid biosynthesis. Clavulanic acid is of significant chemical importance as a potent inhibitor/inactivator of β-lactamase enzymes, a prominent means of bacterial resistance to, for example, penicillin. Primary and α-secondary T(V/K) kinetic isotope effects have been determined in earlier work for the clavaminate synthase-catalyzed oxidative cyclization of proclavaminic acid, one of the three reactions mediated by this enzyme. In this paper the β-secondary deuterium kinetic isotope effect for this reaction has been determined using remote 3H and 14C labels in an attempt to distinguish between radical or cationic intermediates in the reaction as suggested by the magnitudes of the primary and secondary α-effects. The presence of the adjacent azetidinone nitrogen and the intervention of an azetinone intermediate, formally antiaromatic in the resonance form of the amide, make interpretation of the low β-secondary effect (1.056 ± 0.002 for dideuteriation at C-3′) problematic. To assist interpretation of this result, a 4-chloroazetidinone model system has been constructed dideuteriated at C-3 identically to proclavaminic acid and bearing remote radiolabels. Reaction of this substrate at 25°C under both radical and solvolysis conditions afforded β-secondary kinetic isotope effect data for direct comparison to the enzymic reaction. The measured effects are similarly small but strongly dependent on the polarity/acidity of the reaction medium. These results are discussed in terms of the commitment to catalysis and the extent to which amide resonance may be favored in the transition state of the oxidative cyclization.
Investigation of the Stereospecificity of Clavaminic Acid Synthase in the Desaturation of Dihydroclavaminic Acid to Clavaminic Acid
Baldwin, Jack E.,Adlington, Robert M.,Crouch, Nicholas P.,Drake, David J.,Fujishima, Yoshiyuki,et al.
, p. 1133 - 1134 (2007/10/02)
Incubations of (4R)- and (4S)--proclavaminic acid with clavaminic acid synthase resulted in the stereospecific removal of the deuterium and hydrogen respectively from C-4, in their conversions to clavaminic acid, suggesting an enzyme catalysed syn-
A Substrate Analogue Study on Clavaminic Acid Synthase: Possible Clues to the Biosynthetic Origin of Proclavamic Acid
Baldwin, Jack E.,Lloyd, Matthew D.,Wha-Son, Byeng,Schofield, Christopher J.,Elson, Stephen W.,et al.
, p. 500 - 502 (2007/10/02)
Incubation of (2S)-5-amino-(2'-oxoazetidin-1'-yl)pentanoic acid with clavaminic acid synthase gave (2S)-5-amino-2-(2'-oxoazetidin-1'-yl)pent-3,4-enoic acid as the major product, together with a small amount of proclavaminic acid; modification of the amino
ISOLATION OF DIHYDROCLAVAMINIC ACID, AN INTERMEDIATE IN THE BIOSYNTHESIS OF CLAVULANIC ACID
Baldwin, Jack E.,Adlington, Robert M.,Bryans, Justin S.,Bringhen, Alain O.,Coates, Janice B.,et al.
, p. 4089 - 4100 (2007/10/02)
A primary isotope effect was utilised in an in vitro study to allow the isolation and characterisation of an intermediate between proclavaminic acid and clavaminic acid, in clavulanic acid biosynthesis.
Stereochemical Correlation of Proclavamimic Acid and Syntheses of erythro- and threo-L-β-Hydroxyornithine from an Improved Vinylglycine Synthone
Krol, Walter J.,Mao, Shin-shan,Steele, Diana L.,Townsend, Craig A.
, p. 728 - 731 (2007/10/02)
The Hanessian method to prepare the N-Cbz-L-vinylglycine methyl ester has been improved to obtain reproducibility an alternately protected version of this useful synthon in optically pure, crystalline form.A nitrone cycloaddition route has been developed
Studies on the Biosynthesis of Clavulanic Acid. Part 4. Synthetic Routes to the Monocyclic β-Lactam Precursor, Proclavaminic Acid
Baggaley, Keith H.,Elson, Stephen W.,Nicholson, Neville H.,Sime, John T.
, p. 1513 - 1520 (2007/10/02)
Aldol condensation of 3-substituted propionaldehydes with the lithium enolate of ethyl or benzyl(2-oxoazetidin-1-yl)acetate yielded derivatives of proclavaminic acid.The proportion of the threo diastereoisomer in the aldol product could be increased by th
Studies on the Biosynthesis of Clavulanic Acid. Part 5. Absolute Stereochemistry of Proclavaminic Acid, the Monocyclic Biosynthetic Precursor of Clavulanic Acid
Baggaley, Keith H.,Elson, Stephen W.,Nicholson, Neville H.,Sime, John T.
, p. 1521 - 1533 (2007/10/02)
Proclavaminic acid (1) was synthesized by a route which indicated its constitution to be (2S,3R)-5-amino-3-hydroxy-2-(2-oxoazetidin-1-yl)valeric acid.The spectroscopic properties of the synthetic material were identical with those of natural proclavaminic acid, and, like the natural product, it was converted into clavaminic acid (2) by clavaminic acid synthase.An efficient synthesis of 3-hydroxyornithine derivatives was devised which allowed the separation of diastereoisomers and the resolution of a threo compound by the acylase from Escherichia coli.The β-lactam ring was subsequently elaborated by Michael addition of a protected 3-hydroxyornithine to acrylic acid followed by ring closure using triphenylphosphine/di-2-pyridyl disulphide.Model reactions were carried out with enantiomerically pure threonine derivatives to confirm that the formation of the β-lactam moiety did not impair the integrity of the α- and β-chiral centres and that the enzymatic deacylation reaction was capable of resolving the α-centre of an α-amino-β-hydroxy acid.The enantiomeric purity of intermediates was determined using HPLC, 1H NMR spectroscopy utilising the chiral solvating reagents (R)- and (S)-1-(9-anthryl)-2,2,2-trifluoroethanol, and chiral GLC techniques.
