Of carpetimycins

Completion of the formal synthesis of ( + ) carpetimycin A 48 was effected by tributyltin hydride reduction of the bromohydrin 43, to give predominantly the required cis a-hydroxyalkyl P-lactam 46 in 63% yield, together with the... 

Subsequently, other structural variations were reported encompassing compounds such as PS-5 (5) (5), carpetimycin A (6) (6), asparenomycin A (7) (7), and pluracidomycin A (8) (8), from a wide variety of streptomycete strains. Following these stmctures the simplest member of the series, having the completely unsubstituted nucleus, (1, X = CH2), was isolated from bacterial strains of Serratia and Ervinia (9). AH other natural products reported have substituents at both the C-6 and C-2 positions of the bicycHc ring system. Differences in the nature and stereochemistry of these substituents has provided a wide variety of stmctures, and over forty variations have been reported and comprehensively Hsted (10). 

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously deterrnined from the ene-lactam (16). The resultant (R)-aspartic acid (17) demonstrated that the absolute stereochemistry at C-5 of thienamycin is (R), corresponding to that found in the C-5 position of both penicillins and cephalosporins. Confirmation of the stereochemical assignments in both thienamycin (2) and the olivanic acid MM 13902 (3, n = 0) has been confirmed by x-ray crystallography (19,21,22). The stmctural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

The sulfated compounds MM 13902 (3, n = (5) and MM 17880 (4) are also broad-spectmm agents, but not as potent as thienamycia and all lack any significant activity against Pseudomonas (73). Many carbapenems are excellent inhibitors of isolated P-lactamases, particularly the olivanic acid sulfoxide MM 4550 (3, n = 1) (3). The possible mechanism of action of the carbapenems as inhibitors of P-lactamases has been discussed in some detail (74). Other carbapenems such as PS-5 (5) (75), the carpetimycins (76), asparenomycins (77), and pluracidomycins (8) are all highly active as antibiotics or P-lactamase inhibitors. The parent nucleus itself (1, X = CH2) is intrinsically active, but chemically unstable (9). 

The development of antibacterial chemotherapy during the past 75 years has spearheaded the successful use of today s drugs to combat bacterial infections. Studies in (3-lactam chemistry were stimulated when (3-lactam ring, the four membered heterocycle, was recognized as a key structural feature as well as a key therapeutic feature of the bicyclic (3-lactam antibiotics such as penicillins, cephalosporins, and other classical antibiotics. The last two decades have registered the discovery of several nonclassical bicyclic (3-lactam antibiotics, e.g., thienamycin and carba-penems of natural origin like olivanic acids, carpetimycin, pluracidomycin, and aspareomycins. 

The microorganism Streptomyces olivaceus produces a number of P lactam antibiotics and P-lactamase inhibitors which have collectively become known as the olivanic acids 49, 69—75). Together with other streptomycete metabolites such as thienamycin 80, 81), PS-5 85, 86), the carpetimycins 90, 91) and the asparenomycins 92), they form a family of natural products characterised by the presence of the l-carbadethiapen-2-em (7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid) ring system (94). The simplest member of the family is the completely unsubstituted nucleus (94), recently isolated from various species of Serratia and Erwinia 98). All the other natural products possess substituents at C(2) and C(6) of this nucleus, the former being attached by way of a sulphur linkage. Differences in the nature and stereochemistry of these substituents have provided a wide variety of structures. Almost forty natural variations of this ring system are now known and these are listed in Table 5. 

Independently of the work on the olivanic acids, researchers at the Merck Company had isolated, and determined the structure of, the related compound thienamycin (107) produced by Streptomyces cattleya 80,81). Here a free amino group is present, while the configuration at C(8) is R). An extensive review of all aspects of the chemistry of thienamycin has recently been published (103). Two derivatives of thienamycin found in the same fermentation broth were iV-acetyl thienamycin (108) (81, 82) and N-acetyldehydro-thienamycin (109) (81, 83). Workers at Merck have also isolated from Streptomyces flavogriseus various epithienamycins (A to F), which correspond to the olivanic acids (77). Subsequently discovered by numerous Japanese workers were PS-5 (110) (85,86), carpetimycin A (111) (90,91), asparenomycin A (112) (92) and the many other compounds listed in Table 5. 

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