Thienamycin structure

Fig. 5.5 A, clavulanic acid B, latamoxef C, 1-carbapenems D, olivanic acid (general structure) E, thienamycin F, meropenem G, 1-carbacephems H, loracarbef.

Thienamycin (Fig. 5.5E) is a broad-spectrum /3-lactam antibiotic with high /3-lactamase resistance. Unfortunately, it is chemically unstable, although the TV-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 5.5E) is stable to most/3-lactamases but it readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropenem, which has yet to be marketed, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 5.5F. 

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). 

The discovery of thienamycin created great excitement it is a structurally novel P-lactam antibiotic of outstanding potency and has a remarkable spectrum of activity. It was the broadest spectrum antibiotic of its day. There was, however, a major problem thienamycin is not a stable molecule. Merck scientists were faced with the touchy problem of modifying thienamycin chemically to create a stable molecule while maintaining all its remarkable properties. Following considerable effort, they... 

Other P-lactam antibiotics have revolutionized our understanding of the structure-activity relationships in this large group of antibiotics. Thienamycin (9.53), discovered in 1976, is a broad-spectrum antibiotic of high activity. It is lactamase resistant because of its hydroxyethyl side chain but is not absorbed orally as it is highly polar. Unfortunately,... 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin have been prepared primarily to study structure-activity relationships. 

Further, the discovery of 7-a-methoxy cephalosporins [5] from Streptomyces in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic (3-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic (3-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the (3-lactam research with the recent discovery of tricyclic (3-lactam antibiotics called trinems [14]. Thus, (3-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1). 

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 successive discoveries of cephalosporin C (1945), cephamycin (1971), thienamycin (1976), clavulanic acid (1975), nocardicin (1976), sulfazecin (1981), etc. The structural diversity found in the natural compounds inspired the medicinal chemists for side-chain modifications of the penam and penem cores (see Section 2.03.11). 

There are now large numbers of p-lactam antibiotics known and one family has the opposite (trans) stereochemistry around the four-membered ring. The typical member is thienamycin. We will analyse the spectrum in a moment, but first look at the differences—apart from stereochemistry—between this structure and the last. The sulfur atom is now outside the five-membered ring, the acid group is on a double bond in the same ring, and the amino group has gone from the [3-lactam to be replaced by a hydroxyalkyl side chain. 

Although much of the work on the microbial hydroxylation of amides has been directed at active-site m ing of the enzyme responsible, the products themselves are valuable building blocks for further synthesis, for example, for various optically active sesquiteipenes or -lactams. In this latter context regioselective hydroxylation of unactivated positions is particularly attractive as several -lactam antibiotics, e.g. the carbapenem derivative thienamycin, have a free hydroxy group in their structure. 

Albers-Schoenberg G, Arison BH, Hensens OD, Hirshfield J, Hoogsteen K, Kaczka EA, Rhodes RE, Kahan JS, Kahan EM, et al. Structure and absolute configuration of thienamycin. J. Am. Chem. Soc. 1978 100 6491-6499. 

This method can be effectively applied to the preparation of /S-lactam compounds. The ester enolate-imine condensation approach to j8-lactam formation has been developed over the past decade. Thienamycin and related carbapenems have been the focus of particular attention because of their structural uniqueness and potent antibacterial activity. 

The big surprise concerning the structure of thienamycin is the missing sulfur atom and acylamino side-chain, both of which were thought to be essential to antibacterial activity. Furthermore, the stereochemistry of the side-chain at substituent 6 is opposite from the usual stereochemistry in penicillins. 

The olivanic acids (e.g. MM13902) (Fig. 10.56) were isolated from strains of Strepto-myces olivaceus and are carbapenam structures like thienamycin. They have very strong 3-lactamase activity, in some cases 1000 times more potent than clavulanic acid. They are also effective against the 3-lactamases which can break down cephalosporins. These 3-lactamases are unaffected by clavulanic acid. 

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously determined 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 structural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study structure—activity relationships (24). The most interesting class of N-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while gready increasing the chemical stability. Thus N-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C12H17N304S, (25) was chosen for clinical evaluation and... 

---