Synthetic Carbapenem Antibiotics. I. 1-b-Methylcarbapenem

Abstract

A total synthesis of a novel I-B-methylcarbapenem antibiotic, (-)- -(1&,5~,6~F2-(2-~~-dimethylemino-2-iminoethylthio~6~(l&j-l-hydroxyethyi~l-met~ ylcarbapen-2-em-3-carboxyiic acid 1, is reported.Compound 1 is highly resistant to renal dipeptidase-I yet retains the excellent antibacterial activities of N-formimidoylthienamycin.Since the discovery of thienamycin, many natu?elly occurring and synthetic carbapenem antibiotics have been reported.lThe main thrust of this structural modification work has been directed toward elaborating various new substituents a t position C-2 and C-6 on the bicyclic cerbapenem nucleus.Nevertheless, none of these carbapenem antibiotics has simultaneously overcome the deficiencies of thienamycin, i & , chemical instability at.high concentration and susceptibility t o renal dipeptidase-12 while retaining its excellent antibacterial activity.In the search for a chemically and metabolically stable carbapenem antibiotic, we have undertaken a program directed toward the synthesis of 1-substituted carbapenems.Though a few 1-substituted carbapenems have been reported recently,3 they either do not have optimal substituents a t C-2 and C-6 positions of the carbapenem ring system or are devoid of the antibacterial activity of thienamycin.Herein, we wish t o report the total synthesis of exceptionally stable and potent 1.2.6-trisubstituted carbapenem antibiotics.a novel 1-0-methyicarbapenem, (-~(1~5~6~)-2-(2-~~-dimethylamino-2-iminoethylthio~-&~~l~Fl-hydro~-ethyl>l-methylcarbepen-2-em-3-carboxyiic acid 1.