Carbapenem derivatives

Recently, a structure-inhibition-activity relationship study revealed that carbapenem derivatives could lead to a new class of specific inhibitors of bacterial /3-lactamases [54], Indeed, phosphonyl derivatives, 5.16, and their cyclic analogues, 5.17 - i.e., structures not based on the /1-lactam nucleus -can also afford effective inhibitors of /3-lactamases [55][56],... 

Hatanaka and co-workers found that carbapenem derivatives were readily available by means of an Ugi-4CR between 3-aminoglutaric acid mono-t-butyl ester, formaldehyde, and 4-nitrobenzyl isocyanide that gave the /l-lactam 156, which was converted into the 4-nitrobenzyl ester 157. The subsequent stereoselective Dieckmann condensation allowed the preparation of the 2-oxocarbapenem derivative 158 (Scheme 2.57) [87]. 

A palladium-catalyzed C-N bond-forming reaction of the azetidin-2-ones 375 formed the carbapenem derivative 376 (Equation 149) <2002TL111>. 

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. 

Application of the above screen led to the detection of a number of /8-lactamase inhibitors from a number of strains of Streptomyces olivaceus. They were identified as the carbapenem derivatives, MM 13902 (12), MM 4550 (13) and MM 17880 (14), known collectively as the olivanic acids [27, 28]. Not only are they potent -lactamase inhibitors, but are also powerful antibacterial agents. Subsequently, a whole series of carbapenem derivatives... 

In the hydrogenated series the synthesis of carbapenem derivatives 121 by desulfurization with PPha was reported (93EUP559533) (Scheme 33). 

Because they cause prolonged inactivation of certain fi-lactamases. class I inhibitors ate particularly useful in combination with extended-spectrum, lactamase-sen.sitive penicillins to treat infections caused by lactamase-producing bacteria. Three such inhibitors, clavulanic acid, sulbactam, and tazobactam. are currently marketed in the United States for this purpose. A class II inhibitor, the carbapenem derivative imipenem. has potent antibacterial activity in addition to its ability to cause transient inhibition of some /3-lactamases. Certain antibacterial cephalosporins with a leaving group at the C-3 position can cause transient inhibition of lactamases by forming stabilized acylenzyme intermiediates. These are discu.ssed more fiilly below in this chapter. 

Sakya ef al. reported the preparation of novel tricyclic diazo carbapenem derivatives 236, where one of the key steps in their synthesis involved cycloaddition of 3,6-bis(methylthio)-l,2,4,5-tetrazine 125 to alkynyl azetidinone 234, which gave the corresponding pyridazine 235. Attempted preparation of analogs of 235 via reaction of 125 with vinyl azetidinone analogs of 234 resulted in the formation of undesired rearrangement products (Scheme 60) <1997TL5913>. 

The ability of L-Pro to promote aldol and Mannich reactions has also been exploited with chiral starting materials wherein L-Pro is not controlling the stereochemical outcome of the product, but rather substrate control is operative. The efficiency of the procedure prevents the use of other similar catalysts for these transformations. As an illustration, aldol and Mannich reactions have been employed to prepare carbapenem derivatives with potential value for the preparation of new antibacterial agents (Scheme 2.11). 

---