Carpetimycin A

[formula: see text] Cycloaddition between gamma,delta-unsaturated beta-enamino ester 9 and camphor-derived oxazoline N-oxide 8 afforded a single adduct, 14. Dipolarophile 9 proved to be very reactive despite the substitution on the double bond. Stereoselective sodium cyanoborohydride reduction of the imminium intermediate 14a gave rise stereoselectively to beta-amino ester derivative 15a. Oxidative acidic hydrolysis, oxidation of the resulting aldehyde 18, deprotection, and cyclization afforded the beta-lactam 23, a direct precursor of (+)-carpetimycin A.

Retrosynthesis was carried out to generate, from a target molecule, a symmetric diester in the prochiral or meso form. The symmetric diester was subjected to asymmetric hydrolysis with pig liver esterase to create the corresponding chiral half-ester. The chiral half-ester was converted into the target molecule by organic synthesis. Thus, various types of carbapenem antibiotics, negamycin, showdomycin, 6-azapseudouridine, cordycepin, aristeromycin, neplanocin A, and precursors of fortimicin were efficiently synthesized with the desired absolute configuration. The methods for asymmetric synthesis starting from substrates with sigma-symmetry have been extensively developed.

By applying the synthetic process reported in our previous paper, we synthesized new carbapenems having various (substituted) thio and alkoxy groups at the C(3) position and 1-hydroxy-1-methylethyl and analogous groups at the C(6) position with cis- and trans-stereochemistry; the in vitro antibacterial and beta-lactamase inhibitory activities of these new carbapenems were examined. Compared to C-19393 H2, some of these compounds (e.g., 11A-a-3 approximately 5) showed improved in vitro antibacterial activity especially against Pseudomonas aeruginosa; they showed a strong beta-lactamase inhibitory activity as well. Two noteworthy effects of substituent variation at the C(6) position on the activities were observed: 1) the trans-configuration caused a definite loss; and 2) introduction of 1-hydroxycyclobutyl and 1-hydroxy-1-methylpropyl groups in place of the 1-hydroxy-1-methylethyl group caused a diminution. The carbapenem (13A-a-2) with an alkoxy group at the C(3) position had a marked decrease in activity compared to the corresponding thio-substituted carbapenem (11A-a-12).