Thienamycin carbapenem antibiotic

Ketene has also been used on a large scale for C-acetylation in the synthesis of the carbapenem antibiotic thienamycin [59995-64-1] (86,87). 

Additions of organometallic compounds to 2-azelidinones such as 1 or 4 bearing a leaving group in the 4-position preferentially or exclusively afford tram-3,4-substituted /(-lactams 3 or 6. Therefore, the participation of an A -acylinline intermediate such as 2 or 5 which is attacked from the less hindered side is probable14-16. This has been exploited for the synthesis of carbapenem antibiotics, e.g., thienamycin (7)16. 

H. Kropp, J. G. Sundelof, R. Hajdu, F. M. Kahan, Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase I , Antimi-crob. Agents Chemother. 1982, 22, 62-70. 

This insertion reaction has provided a stereocontrolled synthesis of ( + > thienamycin (3), an important carbapenem antibiotic.5... 

Ratcliffe, R.W and G. Albers-Schonberg The Chemistry of Thienamycin and Other Carbapenem Antibiotics" and I. Ernest. The Penems" in R.B. Morin and M. Gorman, cds.. Chemistry and Biology of ft -Iatcrum Antibiotics. Academic Press, New York, 1982. Chapts. 4 and 5... 

A formal total synthesis of the early carbapenem antibiotics thienamycin 217 and PS-5 218 from an acyclic amino acid derivative has been reported <1996JOC2413>. For a cycloaddition process from acyclic compounds, see Section... 

Kropp H, Sundelof JG, Hajdu R, Kahan EM. Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase-1. Antimicrob Ag Chemother 1982 22 62-70. 

Carbapenem SQ 27860 (5i )-7-oxo-l-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 5 was the first carbapenem antibiotic produced by bacteria. It shows a wide antibacterial spectrum and it is unstable, but it can be characterized as its p-nitrobenzyl ester. (-l-)-Thienamycin (6), 8-ep/-thienamycin (7), olivanic acids " and (- -)-PS-5... 

Takashi Kamiya, Hatsuo Aoki, and Yasuhiro Mine The Chemistry of Thienamycin and Other Carbapenem Antibiotics Ronald W. Ratcliffe and Georg Albers-Schdnberg The Penems Ivan Ernest Clavulanic Acid... 

Little has been published on the biosynthesis of the carbapenem antibiotics. Albers-Schonberg et al. 281) reported that the carbapenem nucleus in thienamycin is derived from glutamate and acetate as shown in Fig. 6, but so far no detailed account of this work has been published. Box... 

Rosi, D., M. L. Drozd, M. F. Kuhrt, L. Terminiello, P. E. Came, and S. J. Daum Mutants of Streptomyces cattleya Producing N-Acetyl and Deshydroxy Carbapenems Related to Thienamycin. J. Antibiotics 34, 341 (1981). 

Kametani, T Synthesis of Carbapenem Antibiotics. Heterocycles 17, 463 (1982). Shiozaki, M., and T. Hiraoka A Stereocontrolled Formal Total Synthesis of ( )-Thienamycin. Tetrahedron 38, 3457 (1982). 

Shih DH, Cama L, Christensen BG. Synthetic carbapenem antibiotics.3. 1-Methyl thienamycin. Tetrahedron Lett. 1985 26 587-590. 

Occurrence, Fermentation, and Biosynthesis. Although a large number of Streptomjces species have been shown to produce carbapenems, only S. cattkja (2) and S. penemfaciens (11) have been reported to give thienamycin (2). Generally the antibiotics occur as a mixture of analogues or isomers and are often co-produced with penicillin N and cephamycin C. Yields are low compared to other P-lactams produced by streptomycetes, and titres are of the order of 1—20 p-g sohdusmL despite, in many cases, a great deal of effort on the optimization of the media and fermentation conditions. The rather poor stabiUty of the compounds also contributes to a low recovery in the isolation procedures. The fermentation and isolation processes for thienamycin and the olivanic acids has been reviewed in some detail (12). 

Extensive carbapenem and penem antibiotic research has been ongoing since thienamycin was discovered in 1978. However, only the imipenem-cilastatin combination has become a commercial product. Launched in 1985 in the United States as a broad-spectmm hospital product under the name Ptimaxin, this product had worldwide sales of some 300 million in 1988. Sales were predicted to rise to 345 million for the year ending 1989 (154). 

There are several naturally occurring variations on the lactam-thiazolidine or lactam-dihydrothiazine structures, leading to other useful antibiotics or to inhibitors of the (5-lactamases, enzymes that hydrolyze the (5-lactam unit. One group, termed carbapenems 5 has a five-membered ring in which the thiazolidine sulfur is replaced with CH2- Such compounds may still contain sulfur in a thioethylamine side chain (derived from L-cysteine) as in thienamycin 6, originally isolated from Streptomyces cattleya (Scheme 2). 

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