.1 Beta-methyl Carbapenem Antibiotic Nucleus Synthesis And Derivatives Of The Design, Synthesis And Biological Activity Evaluation

Carbapenem is a kind ofβ-lactam antibiotics possessing potent antibacterial activities against the widest range of bacteria. 1β-Methylcarbapenem antibiotics have good stability for mostβ-lactam enzymes in vivo, and also resistant to dehydropeptidase-I(DHP-I). Therefore, the synthetic approach of 1β-methylcarbapenem's parent structure is very important.In this study, the core skeleton of 1β-methylcarbapenem IV were constructed. First, we synthesized the intermediate I with cheap L-threonine as the starting material via 6 steps. We prepared the core skeleton IV through two synthetic routes from the intermediate I, and found a convenient method which has good yield and high stereoselectivities.Furthermore, following the "Me-Too" principle, we designed and synthesized two series novel 1β-methylcarbapenem derivatives in order to find new antibiotics.R=1β-methylcarbapenem core structure, R¹=R²=H or CH₃, R³=groups of carbonyl substitutes,.In this thesis, 99 compounds were synthesized, 49 of which are unreported including 7 target molecules. The structure of the finial products and most of the key intermediates were confirmed by NMR, MS, or HRMS.The other achievement in the thesis is analysis of the reaction results. This analysis was combined with quantitative calculation and the mechanism discussion. Additionally, most of these derivatives were tested for the bioactivities, and some of which showed good antibacterial activities. All of the work and results will be meaningful for the synthesis of 1β-methylcarbapenems and also will be helpful for the development of new drugs.