Heteroatom-activated .beta.-lactam antibiotics: considerations of differences in the biological activity of [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids (oxamazins) and the corresponding sulfur analogs (thiamazins)

Abstract

The considerable antibacterial activity of [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids (oxamazins) in contrast to the lack of activity of the corresponding sulfur analogues (thiamazins) is examined in terms of physicochemical parameters, including electronegativity, IR carbonyl stretching frequencies, base hydrolysis rates, and three-dimensional molecular geometries. An X-ray structure determination of a protected thiamazin together with molecular graphics and molecular orbital calculations on model structures reveals that thiamazins would not fit as well as oxamazins in the active site of target bacterial transpeptidases. As a result of thiamazins' long N-S and S-C bond lengths, the pharmacophoric beta-lactam ring and carboxylate functionality cannot adopt the spatial relationship they have in penicillins and cephalosporins. The beta-lactam nitrogen of the monocyclic, crystalline thiamazin is 0.18 A out of the plane of its three substituents, and this distance (h) is predicted by computational chemistry methods to be higher in oxamazins. The rates of beta-lactam ring opening of an oxamazin, thiamazin, and aztreonam are comparable, even though the pyramidal character and IR data both indicate the electronegative oxygen analogue has reduced amide resonance. MNDO, AM1, and MINDO/3 correctly give a twofold potential for rotation about the N-S bond in model sulfenamides, with barrier heights ranging up to 12 kcal/mol.

Studies on Nonconventionally Fused Bicyclic β-Lactams

“…Despite their unusually high electrophilicities, these N−S-fused lactams appear to be quite resistant toward hydrolytic conditions and can be easily isolated from aqueous sodium bisulfite solution and purified by silica gel flash chromatography without any apparent decomposition. They tolerate prolonged exposure to aqueous media ranging from pH 4 to 10 and are thus comparable to the monocyclic thiamazins that have been reported by Miller to be hydrolytically stable below pH 11 …”

“…Sulfenamides can have significant barriers to rotation around the sulfur−nitrogen single bond, generally in the range of 9−23 kcal/mol . Miller and his colleagues have observed this behavior in their studies on the closely related thiamazin β-lactams, whose barrier to sulfur−nitrogen bond rotation was determined to be as high as 12 kcal/mol (Figure ) . In examining the behavior of our β-lactams by variable temperature NMR, however, we found that lactams 38 exist as single compounds over a temperature range of −50 to +50 °C, which suggests that neither of the latter two isomerization phenomena is a factor in the cyclizations of our N -SMe β-lactams.…”

Conversion of Glucuronic Acid Glycosides to Novel Bicyclic β-Lactams

“…The use of chiral pool molecules to prepare β -lactams has become routine. , Within this context, the use of carbohydrates as synthons is especially appealing given the density of functionality in these substrates that can ultimately be incorporated into the final targets . We recognized that the carbohydrate template could be useful for the construction of a number of types of functionalized 3-hydroxy, 3,4-bicyclic, 1,4-bicyclic, and polycyclic β -lactams and oxamazins (Scheme ). The successful incorporation of the inherent oxygen groups and stereochemical information contained in the carbohydrates into the β -lactam system presents intriguing synthetic challenges, the most daunting of which is facile, differential protection of the oxygen functionalities.…”