Stable Oxapenem-3-carboxylic Acids – A New Class of β-Lactam Antibiotics. Influence of 2- and 6-Alkyl Substituents

Abstract

/?-Lactam A ntibiotics, Stable Oxapenem-3-carboxylic Acids, X-Ray N ovel antibacterially active oxapenem-carboxylic acids were prepared. Their increased sta bility depends on the 2-tert-butyl substituent and arises from its electron releasing inductive effect. The geometry and reactivity o f oxapenems are discussed on the basis o f two X-ray structure determ inations and compared to those o f related antibiotics.

Acyclic Twisted Amides

“…As expected, the average values of N-pyramidalization and twist are slightly lower as compared to β-lactams by χ N , 8.5° and τ: 7.5°, respectively, − which is a consequence of less strained five-membered fused ring system. Similarly, the highest reported χ N value for a five-membered fused lactam is lower than that of the most N-pyramidalized β-lactam ( 4.248 , 55.6°, and 4.119 , 69.4°, respectively); however, it clearly indicates a predominant sp 3 character of the amide bond nitrogen atom in this ring system. Finally, there is no correlation between N-pyramidalization and amide bond twist in structurally characterized amides constrained in fused five-membered ring systems.…”

“…In general, the amide bond geometry of structurally characterized β-lactams presented in Figures and − can be characterized as N-pyramidalized (average χ N of 54.4°), while twist is less significant (average τ of 19.2°), as expected from the geometry of the fused four-membered ring system. There is only a very scattered correlation between N-pyramidalization and twist of the amide bond, with the general trend of higher twist with increased nitrogen pyramidalization ( R 2 = 0.30).…”

“…The most common are [ 2 .4.0] and [ 2 .3.0] ring systems with the six-membered ring such as 1,3-oxazinane (e.g., 4.30 ), and more common five-membered ring, such as thiazolidine 1,1-dioxide (e.g., 4.32 ), thiazolidine 1-oxide (e.g., 4.33 ), thiazolidine (e.g., 4.34 ), 1,3-selenazolidine (e.g., 4.36 ), pyrrolidine (e.g., 4.81 ), imidazolidine (e.g., 4.94 ), or oxazolidine (e.g., 4.101 ) . In general, more dense substitution of the fused ring, in particular at the α-positions to the nitrogen atom and the carbonyl group and ring unsaturation, result in higher N-pyramidalization. − These N-pyramidalized amides are well-known to be highly reactive as acylating reagents and are important pharmacophores in medicinal chemistry research.…”