Norcardicins

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 discovery of the norcardicins and monobactams demonstrated for the first time that a conformationally constrained bicyclic structure was not necessary for antibacterial activity of (3-lactams [12, 13]. In recent years, various natural and unnatural monocyclic-(3-lactams have been shown to exhibit high biological activity, suggesting that the biological activity of the particular ring is influenced by the type of substitution attached to the azetidin-2-one ring (Fig. 2). 

Nonapeptide hnear amides are also often synthesized using the carbodiimide method. Examples include the synthesis of norcardicine A and the synthesis of renin inhibitors. The total synthesis of a trifluoromethyl (Tfm) analogue of pepstatin uses EDCCl/HOBt in the condensation steps. ... 

The importance of j -lactams in the penicillins , cephalosporins , thienamycin and the recent discovery of antibiotic activity among monocyclic j -lactams such as norcardicins or the )5-lactamase inhibitor clavulanic acid have recently intensified research toward the synthesis of this system . Among the different procedures that have been developed for incorporating a 2-azetidinone unit , the ring expansion of cyclopropanol amines provides a simple and convenient route to these attractive small ring compounds. 

Apart from numerous similar 3-lactam syntheses,the very promising photolytic [2 + 2] cycloaddition of imines (or the corresponding hexahydro-l,3,5-triazenes respectively)to chromium carbene complexes that leads to norcardicin precursors merits special interest. 

Serine is the precursor of several antibiotics. The oxazole ring of the antibiotic virginiamycin Mj 100(Scheme 31)is derived from serine incubation of Streptomyces virginiae with samples of (2S, 3R)- and (2S, 3S)-[3- Hi]serine, derived as in Scheme 18, showed that the 3-pro-S hydrogen of serine is lost on formation of the double bond (107). This implies anti dehydrogenation, a process more commonly found to be syn. The -lactam antibiotic nocardicin 101 is biosynthesized from serine, and incubation of Nocardia uniformis with stereospecifically deuterated serines, prepared by the method outlined in Scheme 21, has yielded samples of norcardicin, the NMR spectra of which indicated that ) -lactam ring formation occurs with inversion of configuration (108, 109). 

N-Alkylation of P-lactams has been carried out using PTC (Scheme 18). This is an important step in the synthesis of norcardicin. 

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