Stereoselective synthesis of optically active bicyclic β-lactam carboxylic acids that target pilus biogenesis in pathogenic bacteria

Hans Emtenäs, Marcus Carlsson, Jerome S. Pinkner, Scott J. Hultgren, Fredrik Almqvist

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22 Scopus citations

Abstract

Optically active bicyclic β-lactams were synthesized, starting from 2-H-Δ2-thiazolines and Meldrum's acid derivatives. Several methods to accomplish an ester hydrolysis without damaging the β-lactam framework were investigated. A rapid CsOH saponification of the β-lactam methyl esters was developed and protonation of the Cs-carboxylates by Amberlite (IR-120 H+) afforded a series of bicycle β-lactam carboxylic acids. Moreover, a convenient method for the synthesis of 2-H-Δ2-thiazolinecarboxylic acid methyl ester 2 was developed. Bicyclic β-lactam carboxylic acids 7a-g and aldehydes 4a-d were screened for their affinity to the bacterial periplasmic chaperone PapD using a surface plasmon resonance technique. β-Lactams substituted with large acyl substituents showed better binding to the chaperone than the native C-terminal peptide PapG8, demonstrating that bicyclic β-lactams constitute a new class of potential bacterial chaperone inhibitors.

Original languageEnglish
Pages (from-to)1308-1314
Number of pages7
JournalOrganic and Biomolecular Chemistry
Volume1
Issue number8
DOIs
StatePublished - Apr 21 2003

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