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

• Optically active bicyclic -lactams were synthesized, starting from 2-H-2-thiazolines and Meldrum's acid derivatives. Several methods to accomplish an ester hydrolysis without damaging the -lactam framework were investigated. A rapid CsOH saponification of the -lactam methyl esters was developed and protonation of the Cs-carboxylates by Amberlite (IR-120 H+) afforded a series of bicyclic -lactam carboxylic acids. Moreover, a convenient method for the synthesis of 2-H-2-thiazolinecarboxylic acid methyl ester 2 was developed. Bicyclic -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. -Lactams substituted with large acyl substituents showed better binding to the chaperone than the native C-terminal peptide PapG 8, demonstrating that bicyclic -lactams constitute a new class of potential bacterial chaperone inhibitors.

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