Total Synthesis Of Carbapenem Antibiotic Imipenem

Thienamycin,as a metabolite of Streptomyces cattleya discovered in 1976, is the first antibiotic with carbapenem nucleus. It is a zwitterionic compound carrying an arninoethylthio substitutent in the 2-position and a 1'-hydroxyethyl substitutent in the 6- position of carbapenem nucleus. The absclute stereochemistry at the three chiral centers is 5R,6S and SR. lmipenem,a N-formimidoyl derivative of thienamycin,has been used in clinical treatment of severe bacterial Infections. It is one of the best antibacterial antibiotics at present. A new thienamycin producer-Streptomyces cattleya C-5676 had been found by researchers in our Institute in 1987,consequently thienamycin and imipenem were obtained by fermentation and by semisynthesis respectively. But thienamycin is chemical unstable, it degrades via dimerisation; and also by action of enzyme dehydropeptidase (DHP-1)which exists in human kidney.So imipenem can only be used cilinically together with Cilastatin, the DHP- I inhibitor. In order to realize an industrial method for imipenem preparation, study its structure-activity relationship,and find out better carbapenem antibiotics via structure modification, we began our study on the total synthesis of carbapenem antibiotic namely imipenem.As a result of retrosynthesis thienamycin,the total synthesis of imipenem can be divided into two major parts: (1) preparation of an azetidinone precusor with same configurations as natural product and suitable substitutents for consequent formation of the second ring ; (2) construct the second ring and make it as a properly functionallized carbarpenem. Finally, the total synthesis of imipenem was accomplished by us according to the following procedures:1.Preparation of racemic azetidinone via [4+2] Diels-Alder approach.(Scheme3,page31).The diene(12), prepared through two steps from ethyl acetylacetate, was reacted with n-butylvinyl ether to give two new 2H-pyran derivatives (13) and (14) in quantitative yield. Their ratio of (13) and (14) was 2:3. Their relative configurations were established as (2α,4β) for (13) and (2β,4β) for (14) respectively by ~1H-NMR(500MHz). The reduction of (13) was achieved by high pressure hydrogenation with freshly prepared Raney nickel as catalyst,and the product (15) with (2α,4α,5α ,6 α ) configurations was obtained. Starting from (15) two routes were used for synthesis of azetidinone(22). Route A: semiacetal (16) was obtained by selective hydrolization of (15),then oxidized to lactone (17) or acid (18) by chromic acid, (17)/(18) was hydrolized to give (20). Without separating, (20)...