Design and synthesis of a novel class of constrained tricyclic pyrrolizidinone carboxylic acids as carbapenem mimics.
A series of tricyclic pyrrolizidinone carboxylic acids harboring an angular methano group were synthesized as mimics of carbapenems and carbapenams. A key reaction involved a novel intramolecular cyclopropanation mediated by a trimethylstannylmethyl group and an adjacent iminium ion. Enolate chemistry on a tricyclic lactam ring unit allowed the introduction of various substituents. Further elaboration afforded tricyclic pyrrolidinone carboxylic acids, which were found to be inactive as inhibitors against a panel of bacterial strains. However, the antibacterial activity of ceftazidine was enhanced in the presence of the tricyclic analogues.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec H3C 3J7, Canada. stephen.hanessian@umontreal.ca
Buckle
Ronald
R
Bayrakdarian
Malken
M
D015780:Carbapenems / Q000138:chemical synthesis* / Q000737:chemistry*; D002384:Catalysis; D002442:Ceftazidime / Q000494:pharmacology; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D015394:Molecular Structure; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis* / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015780:Carbapenems; D011084:Polycyclic Aromatic Hydrocarbons; D011758:Pyrroles; D002442:Ceftazidime