Synthesis, Stability, and Antimicrobial Activity of (+)-Obafluorin and Related β-Lactone Antibiotics

Article abstract of DOI:10.1021/jo00092a025

Optically pure obafluorin (1), an antibacterial agent from Pseudomonas fluorescens, was synthesized in six steps via lactonization of N-<(nitrophenyl)sulfenyl>-(2S,3R)-2-amino-3-hydroxy-4-(4-nitrophenyl)butanoic acid (12a), which was prepared in a stereospecific manner from 4-nitrophenylacetaldehyde (9a) and (S)-1-benzoyl-2-tert-butyl-3-methyl-4-imidazolidinone (7).A series of analogues was then synthesized in order to probe structural features required for antibacterial activity as well as those responsible for the hydrolytic decomposition of 1 to the corresponding hydroxy acid 23a.Analogues 22b and 22c wherein the nitro group of 1 is replaced with hydrogen and chlorine, respectively, were prepared in a fashion similar to 1, as were the N-acetyl, N-benzoyl, and N-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetyl (ATMO) derivatives 24a-c.The tosylate salt of L-threonine-β-lactone (21) was transformed to a series of N-acylated derivatives including the following: 22d (2,3-dihydroxybenzoyl), 25 (2-hydroxybenzoyl), 27 (3,4-dihydroxybenzoyl), 29 (4'-methyl-2,2'-bipyridine-4-carbonyl), 31 (ε-(L-α-aminoadipoyl)), 34 ((N'-2,3-dihydroxybenzoyl)-β-alanyl), 35 (bromoacetyl), 36 ((6-purinylthio)acetyl), and 37 ((4-pyridylthio)acetyl).The results show that α-amino β-lactones bearing an N-acyl group with an o- or p-hydroxybenzoyl moiety are especially prone to decomposition under aqueous conditions and that this effect is enhanced by replecement of the 4-nitrobenzyl group on the oxetanone ring of 1 with a methyl.The N-(3,4-dihydroxybenzoyl)-L-threonine β-lactone (27) converts slowly in the solid state to (4S,5S)-2-(3,4-dihydroxybenzoyl)-5-methyl-2-oxazoline-4-carboxylic acid (39b), which hydrolyzes rapidly in 4:1 CD3CN:D2O to O-(3,4-dihydroxybenzoyl)-L-allothreonine (38b).Direct hydrolysis of 27 to 38b under the same conditions has a half-life of 2.4 days.Preliminary assays for antibacterial activity indicate that 29 has nearly comparable activity to obafluorin (1) but is much more stable.The (2-nitrophenyl)sulfenyl β-lactones 14 and 41, as well as the N-(phenylsulfenyl)-L-threonine β-lactone (44), are the most active agents in the biological assays.