Synthesis of the novel monocyclic β-lactam proclavaminic acid

Abstract

Proclavaminic acid has been chemically synthesised and one pure enantiomer separated which was shown to possess identical physicochemical and biochemical properties t o the natural material isolated from Streptom yces cla vuligerus.

Studies on the biosynthesis of clavulanic acid. Part 4. Synthetic routes to the monocyclic β-lactam precursor, proclavaminic acid

“…The reaction mixture was stirred for 0.75 h and then extracted with ethyl acetate (75 ml). The organic layer was washed with saturated aqueous sodium chloride, dried, and evaporated to give a white solid which, after trituration with two aliquots (1 5 ml) of hexane, gave benzyf 3-bromopropionamidoacetate (5) (7).-Pulverised potassium hydroxide (5.05 g, 90 mmol) and tetrabutylammonium bromide (4.84 g, 15 mmol) were suspended in DCM-MeCN (19: 1, 1.5 1). The suspension was stirred vigorously while a solution of benzyl3-bromopropionamidoacetate (5) (21.5 g, 72 mmol) in DCM-MeCN (19: 1,1.5 1) was added during 6 h. The reaction mixture was stirred for a further 30 min, then the insoluble material was filtered off and the filtrate was evaporated to dryness.…”

“…Thus, an aqueous suspension of threo-(15) was hydrolysed with the protease subtilisin Carlsberg [EC 3.4.21.141, with the pH maintained at 6. 5 with addition of dilute base from an automatic titrator. After the addition of a halfmolar equivalent of base there was a sharp decrease in the rate of reaction.…”

Studies on the biosynthesis of clavulanic acid. Part 5. Absolute stereochemistry of proclavaminic acid, the monocyclic biosynthetic precursor of clavulanic acid

“…Acid.-Since the two diastereoisomers of compounds (34) and (35) could now be satisfactorily separated in good yield the next step was to identify the relative stereochemistry of the biologically active diastereoisomer of proclavaminic acid. Both diastereoisomers of proclavaminic acid had been prepared by the direct aldol route described previously 1, 4 although the relative stereochemistry of each isomer could not be assigned.…”

“…(S)-N 5-Benzyloxycarbonyl-N2-( 3-bromopropiony1)ornithine Benzyl Ester (5).-A solution of (5')-N 5-benzyloxycarbonylornithine benzyl ester (12 g, 34 mmol) in water (150 ml) and THF (225 ml) was cooled in ice and stirred while a solution of 3-bromopropionyl chloride (3.4 ml, 34 mmol) in THF (15 ml) was added dropwise during 20 min. The pH was maintained between 6.7 and 7.3 by the addition of saturated aqueous NaHC03.…”

Absolute stereochemistry of proclavaminic acid, the monocyclic biosynthetic precursor of clavulanic acid

“…A synthesis of the bioactive enantiomer of proclavaminic acid which did not enable the absolute stereochemistry to be deduced was also reported. 3 In order to shed further light on the absolute stereochemistry of proclavaminic acid we report here a further synthesis via a resolved (3-hydroxyornithine and elaborating the (3-lactam ring without altering the chiral centres.…”