Thienamycin is a novel beta-lactam antibiotic discovered in 1976 with an extraordinarily borad spectrum of activity against gram-positive and gram-negative bacteria. Of note is its stability against beta-lactamases and the activity against Pseudomonas spp. These outstanding biological properties promise a clincally very useful beta-lactam antibiotic for the treatment of bacterial infections. Since fermentation processes provide only low yields of Thienamycin and emphasis lies on the total synthesis. The novel structure, consisting of a highly strained 1-carbapenem ring system concomitant with three chiral centers has made Thienamycin a special challenge in organic synthesis. The existing literature reveals numerous lengthy, low yield approaches for the synthesis of (+)-Thienamycin. However, a unique and highly steroselective synthesis has been discovered - a novel method, which generates the trans S* configuration in 2-azetidinones at three centers in a one step process.
The specific aim of this research plan, then, is to further develop and expand this unique process. The method involves the addition of dianions of esters of beta-hydroxybutyric acid to imines to form directly 3(1-hydroxyethyl)-2-azetidionones. After inversion of the configuration at CAlpha, Thienamycin-precursors of correct stereochemistry are obtained. With an appropriate choice of imines (functionalized alky, aryl-, alpha, beta unsaturated imines, iminoethers, iminothioethers and cyclic imines) the newly discovered synthesis is intended to accomplish the formation of all important intermediates in 2-4 steps, which are currently used in the total synthesis of Thienamycin. Since the synthetic pathway is also applicable to a chiral synthesis, the continued research will focus on chiral functionalized 2-azetidinones, starting from chiral esters of beta-hydroxybutyric acid, which are readily available. The proposed chiral synthesis, therefore, of 3(1-hydorxyethyl)-2-azetidionones is not only a unique method for obtaining desired precursors for the correct elaboration of (+)-Thienamycin, but also an extremely advantageous one over existing methods, due to its shortened, facile process and its utilization of inexpensive starting materials.
