Synthesis and Antibacterial Activity of Bicyclic Lactam-Lactones

Abstract

The synthesis of a lactam-lactone bicyclic system containing a pyroglutamate subunit proceeds to give the fused lactone system, which is favoured over the spirocyclic lactone alternative. These systems display no or weak antibacterial activity against the test organisms S. aureus and E. coli.Spirocyclic and fused lactone-lactam systems 1 and 2 ( Figure 1) have been of recent interest, both as a result of their occurrence in the salinosporamide, 1 cinnabarimide 2 and oxazolomycin 3 natural products, and of their conformationally well-defined structures, providing useful templates for drug design (e.g. MI-219 which possesses p53:MDM2 inhibitory activity 4 ). Methodology is now well established to access spirocyclic 5 and fused b-lactone-lactam systems, 1,6 and given the ease with which it is possible to prepare highly functionalised tetramates using some of our recently reported methodology, 7 it was of interest to examine the possibility of direct lactone formation in a highly functional pyroglutamate nucleus; we have already made use of modified tetramates for the preparation of mimics of oxazolomycin. 8 Figure 1We recently reported that pyroglutamate 3a (Scheme 1) is readily available by kinetically controlled endo-delivery of a dithiane anion to the parent tetramate, 7 and this outcome is different from that obtained by direct aldol cyclisation. 9 It was found that similar endo-phenylacetylide delivery also generates the pyroglutaminol 3b in good yield (92%), the stereochemistry of which was established by NOE analysis (Figure 2) and confirmed by single crystal X-ray analysis (Figure 3). 10 Similar highly chemoselective acetylide additions have been reported. 11 Deprotection of the oxazolidine ring of each of 3a,b using Corey-Reichard conditions 12 gave alcohols 4a,c in excellent yields, and the stereochemistry of 4c was established by single crystal X-ray crystallography (Figure 3). 10 Ester hydrolysis (LiOH, THF, H 2 O, MeOH) of 4a to give acid 4b, which could be easily isolated by acid-base extraction in highly pure form, was followed by b-lactone formation using tosyl chloride-pyridine conditions. Although two possible modes of cyclisation were possible, only fused bicyclic product 5a and not the alternative spirocyclic product was obtained, although their calculated enthalpies are similar at -115.1 kcal/mol and -118.4 kcal/mol, respectively (Spartan), and after optimisation, yields were up to 80%. 13 That b-lactone formation had been achieved was clearly indicated from IR and 13 C NMR analysis (n = 1835 cm -1 and d = 167.5 ppm), but unequivocal assignment of selectivity was possible only with successful characterisation of lactone 5a by single crystal X-ray analysis ( Figure 3). 10 It was found that lactam 5a could be readily acylated by reaction with acetyl chloride and triethylamine to give 5b in 75% yield or methylated using neat methyl iodide and caesium carbonate to give the Nmethyl derivative 5c in quantitative yield, confirmed by IR absorptions at 1810, 1716 and 1689 cm -1 . The preference for the f...