Showing papers on "Thienamycin published in 1996"

Formal Total Syntheses of the β-Lactam Antibiotics Thienamycin and PS-5

Abstract: Chiral nonracemic acetylenic acids of general structure 11, prepared using the Schreiber modification of the Nicholas reaction, have been converted to β-amino acid derivatives of type 12 by a two-step sequence involving Curtius rearrangement followed by oxidative cleavage of the acetylenic bond. Amino acid derivatives 12 are excellent precursors for β-lactams of the carbapenem class, including the important antibiotics thienamycin (1) and PS-5 (4).

Recent advances in the chemistry and biology of carbapenem antibiotics

Abstract: The discovery of the olivanic acids and thienamycin aroused considerable interest amongst medicinal chemists and microbiologists around the world. The susceptibility of these agents to metabolic degradation has, however, been a major obstacle in their development. For many years the only notable success from such intensive research was the combination of imipenem with cilastatin, an inhibitor of the renal dipeptidase enzyme DHP-1. The enormous success of Primaxin for the treatment of a range of life-threatening bacterial infections provided the impetus for the discovery of totally synthetic, non-natural carbapenem derivatives that combine the broad spectrum of antimicrobial activity with stability to enzymatic degradation. This has indeed been realised in the development of meropenem; it possesses the broad spectrum of activity and resistance to beta-lactamases that are embodied in imipenem as well as displaying increased stability to human dehydropeptidases. Most recent research has focused upon the development of carbapenem antibiotics which combine broad spectrum antimicrobial activity and metabolic stability with oral absorption, for the treatment of community-acquired infections. Indeed, the pro-drug esters of the tricyclic carbapenems represent the first significant advance in this respect. However, the increased use of carbapenem antibiotics would undoubtedly accelerate the emergence of carbapenem-hydrolysing enzymes. The ultimate challenge could therefore be the design and synthesis of carbapenem derivatives that are resistant to these metallo-beta-lactamases. Due to the enormous problems encountered in the development of the carbapenem antibiotics, this area of research has, in the past, been described as a battlefield that did not bode well for the future [181]. Primaxin and meropenem proved however that these problems were not insurmountable, and are therefore a testimony to the persistence and dedication of those scientists in their war against bacterial infection.

Cloning and sequencing the isopenicillin N synthetase(IPNS) gene from Streptomyces cattleya

Abstract: Great homology existed between IPNS genes from surphur-containing beta-lactam antibiotics producers including procaryotes and eucaryotes A DNA homologous band was confirmed in S cattleya by Southern blot analysis using IPNS gene from S lipmanii as a probe A recombinant plasmid containing the cyclase gene involved in thienamycin biosynthesis and IPNS gene was obtained by complementary cloning with mutant from S cattleya DNA sequencing revealed that the IPNS gene of S cattleya consists of 963 bp encoding a protein of 321 amino acids with ATG as start codon, TGA as stop codon Pairwise comparison of the predicted amino acid sequences showed 56% and 64% similarity with IPNSs of S clavuligerus and S lipmanii, respectively

Asymmetric Radical Cyclization Leading to β‐Lactams: Stereoselective Synthesis of Chiral Key Intermediates for Carbapenem Antibiotics PS‐5 and Thienamycin.

Abstract: A stereoselective synthesis of β-lactams by 4-exo-trig radical cyclizations of N-[2,2-bis(phenylthio)ethenyl]-α-bromo amides bearing a chiral inductor on the nitrogen atom has been examined. Bromide 8, upon treatment with Bu3SnH in the presence of AIBN in boiling benzene, gave a mixture of (4S)-2-azetidinone 12a and its (4R)-isomer 12b in a ratio of 71:29 and 69% combined yield. Similar treatment of α-bromobutanamide 11 with Bu3SnH afforded trans-(4S)-2-azetidinone 17a as the major product along with its (4R)-isomer 17b (70:30, 77% combined yield). Compound 17a was converted into 24, a chiral key intermediate in the synthesis of (+)-PS-5 (25). The cyclization of bromide 28 bearing an additional stereogenic center [(S)-oxygen functionality] at the side chain proceeded with much higher (4S)-stereoselectivity to give azetidinone 29a as the major product together with its (4R)-isomer 29b in a ratio of 78:22 and 40% combined yield. Compound 29a was converted, via an inversion of the oxygen functionality, into 37, a chiral key intermediate in the synthesis of (+)-thienamycin (38). A possible explanation for the observed diastereoselectivity in radical cyclizations is presented.

Synthesis of a Key Intermediate for Thienamycin and Imipenem Through Stereoselective Two‐Direction Elongation of Asymmetrized Bis( hydroxymethyl)acetaldehyde (BHYMA*).

Abstract: The enantioselective formal synthesis of Thienamycin and Imipenem has been realised through two-direction elongation of the chiral building block bis (hydroxymethyl)acetaldehyde 5 . The generation of the two additional stereocentres has been carried out with excellent diastereoselectivity thanks to two sequential “protecting group controlled” nucleophilic additions. Another key step was represented by the regioselective oxidation of a primary-secondary 1,3-diol to the corresponding β-hydroxyacid.

A Formal Total Asymmetric Synthesis of (+)‐Thienamycin.

Abstract: Synthesis of an enantiomerically pure intermediate to (+)-thienamycin is presented: the pivotal reaction in this sequence is the highly diastereoselective Michael addition of a differentially protected lithium amide.

Formal Total Syntheses of the β‐Lactam Antibiotics Thienamycin and PS‐5.

Abstract: Chiral nonracemic acetylenic acids of general structure 11, prepared using the Schreiber modification of the Nicholas reaction, have been converted to β-amino acid derivatives of type 12 by a two-step sequence involving Curtius rearrangement followed by oxidative cleavage of the acetylenic bond. Amino acid derivatives 12 are excellent precursors for β-lactams of the carbapenem class, including the important antibiotics thienamycin (1) and PS-5 (4).