Thienamycin side chain

This methodology has also been used by Bose, who described the synthesis of the thienamycin side chain [119], the first step of which was a [2+2] cycloaddition under microwave irradiation. Likewise, Khajavi described the reaction of trichloroacetic anhydride with imines [120] with classical heating the reaction requires the use of Fe2(CO)9 as a catalyst, whereas under microwave irradiation a catalyst is not required. 

The strained bicyclic carbapenem framework of thienamycin is the host of three contiguous stereocenters and several heteroatoms (Scheme 1). Removal of the cysteamine side chain affixed to C-2 furnishes /J-keto ester 2 as a possible precursor. The intermolecular attack upon the keto function in 2 by a suitable thiol nucleophile could result in the formation of the natural product after dehydration of the initial tetrahedral adduct. In a most interesting and productive retrosynthetic maneuver, intermediate 2 could be traced in one step to a-diazo keto ester 4. It is important to recognize that diazo compounds, such as 4, are viable precursors to electron-deficient carbenes. In the synthetic direction, transition metal catalyzed decomposition of diazo keto ester 4 could conceivably furnish electron-deficient carbene 3 the intermediacy of 3 is expected to be brief, for it should readily insert into the proximal N-H bond to... 

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). 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

The first carbapenem released for clinical use was imipenem (5.46), a compound with relatively high resistance to microbial /3-lactamases. The addition of the (iminomethyl)amino side chain renders imipenem chemically more stable than thienamycin. But, like thienamycin, imipenem is also easily hydrolyzed by renal dehydropeptidase I, producing a mixture of /3-lactam ring-opened 1-pyrrolidine epimers at C(3) [161], The renal metabolism of imipenem can be minimized by co-administration of cilastatin (5.53), a competitive inhibitor of DHP-I [15 6] [162],... 

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. 

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). 

Nowadays, all the therapeutically relevant penems are equipped with the lf/ 3-hydroxyethyl side chain, characteristic of the thienamycin (carbapenem) family (see Table 1). Accordingly, they are prepared by hemisynthesis from the chiral acetoxyazetidinone 76, which is industrially produced on a large scale by chemical methods (see Section 2.03.9). This chiron plays a similar role as 6-APA for the synthesis of semisynthetic penicillins, but here for the synthesis of non-natural penems and carbapenems <1996T331>. 

Since the target enzymes of penicillins are membrane-bound proteins, an essential condition of antibacterial activity is that the antibiotic must be able to penetrate the outer spheres of the bacterial cell and reach its target in an active form. This problem is closely linked to the phenomenon of bacterial resistance (production of /3-lactamases), and justify the development of semisynthetic penicillins varying in the nature of the acylamino side chain at position C-6, and more recently the development of totally synthetic penems related to thienamycin (see Section 2.03.12.3). 

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. 

The acylamino side-chain is essential (except for thienamycin, see later). 

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. 

---