Nocardicins

In 1976 the Fujsawa Company reported the isolation and characterisation of the new monocyclic P-lactam nocardicin A (1) from the fermentation broth of a strain of Nocardia miformis (7). The antibiotic was 

The nocardicin nucleus 3-aminonocardicinic acid (3-ANA) (7) has not been found in nature, but can be prepared by deacylation of nocardicin C using microbial amidases 10). The first chemical method leading to (7) involved acid treatment of the bisthiourea derivative (8) of nocardicin C 11). A more recent method 12) makes use of the reaction of the oxime grouping of nocardicin A with di-/-butyl dicarbonate. This results in (9) which on treatment with trifluoroacetic acid gives (7). Further confirmation of the structure and stereochemistry of the nocardicins was the identification of the acylamino-derivative (10) derived from 3-ANA, with a compound obtained by partial synthesis from penicillin G 11). Another semi-synthetic approach (75) to the nocardicins from penicillin is by way of the thiazoline (11), the final step being Raney nickel desulphurisation of (12). 

The total synthesis of nocardicin A and its analogues has received considerable attention. One of the first approaches 11,14) made use of the classical keten-imine reaction for construction of the P-lactam ring. Reaction of phthalimido-acetyl chloride with the thioimidate (13) in the presence of triethylamine gave the P-lactam (14). Removal of the sulphvu grouping and deprotection afforded 3-ANA, which could be acylated with the appropriate side-chain acid to give nocardicins D, E and G. Reaction of nocardicin D with hydroxylamine produced nocardicin A. Alternative routes 15,16) utilise triazines such as (15) to provide a source of the imines of type (16). This sequence also removes the necessity of a desulphurisation step. 

In 1978 the Lilly group reported (77) a synthesis of nocardicin A starting from the thiazolidine (17) derived from L-cysteine. Formation of the P-lactam (19) was by intramolecular cyclisation of the chloride (18). 

Elaboration of (19) involved conversion to an oxazoline, ring-opening and chlorination at the 4-position followed by reduction to eventually give the benzyl ester of 3-ANA benzyl ether. Subsequent acylation and deprotection led to nocardicin A. 

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In a similar way, several cephalosporins have been hydrolyzed to 7-aminodeacetoxycephalosporanic acid (72), and nocardicin C to 6-aminonocardicinic acid (73). Penicillin G amidase from Pscherichia coli has been used in an efficient resolution of a racemic cis intermediate required for a preparation of the synthon required for synthesis of the antibiotic Loracarbef (74). The racemic intermediate (21) underwent selective acylation to yield the cis derivative (22) in 44% yield the product displayed a 97% enantiomeric excess (ee). 

There are several mechanistically related ring expansion reactions of cyclopropanones which lead to /3-lactams. The conversion of cyclopropanone to /3-lactam (174) via the cyclopropanolamine (173) (75JOC1505) is just one modification, but it illustrates the strategy of this type of approach (73TL4855, 69JA2375) which has been applied to the synthesis of 3-amino-nocardicinic acid (81JOC2999). 

Nocardicin C 3-Aminonocardicinic and a-aminoadipic acids Pseudomonas schuyikilliensis... 

The nocardicins (A to G) have been isolated from a strain ofNocardia and comprise a novel group of /3-lactam antibiotics (Fig. 5.6A). Nocardicin A is the most active member, and possesses significant activity against Gram-negative but not Gram-positive bacteria. 

Fig. 5.6 A, Nocardicin A B, 3-aminomonobactamic acid (3-AMA) C, aztreonam D, penicillanic acid sulphone (sodium salt) E, / -bromopenicillamc acid (sodium salt) F, tazobactam G, sulbactam.

Nadolol, 110 Nafenopin, 214 Nafomine, 212 NafT-onyl, 213 Nalbuphine, 319 Nalidixic acid, 370, 469 Nalmexone, 319 Nalorphine, 318 Naloxone, 318, 323 Naltrexone, 319 Naranol, 454 Nef reaction, 2 Nefopam, 447 Nequinate, 369 Nexeridine, 17 Nicergoline, 478 Niclos amide, 94 Nifedipine, 283 Nifuratrone, 238 Nifurdazil, 239 Nifurimide, 239 Nifui oxime, 238 Nifurpirinol, 240 Nifurcguinazol, 383 Nifursemizone, 238 Nifurthiazole, 241 Nimazone, 260 Nimorazole, 244 Niridazole, 269 Nisobamate, 22 Nithiazole, 268 Nitronic acid, 2 Nivazol, 159 Nocardicins, 435 Noracymethadol, 58... 

Some types of microorganisms, in particular Chromobacterium violaceum, which in the process of performing vital functions can synthesize specific beta-lactam antibiotics that have a monocyclic structure are called monobactams. Nocardicins, in particular nocardicin A, are examples of such monobactams. 

By analogy with the biogenesis of oximes via oxidation of amino acids or biogenic amines, the biosynthetic pathway for insertion of the ketoxime function into the antibiotic, nocardicin A (18), was shown to be dependent on the oxidation of the corresponding primary amine precursor of 18 by cytochrome PTSO ". Similarly, the formation of the ketoxime bond of verongamine (17) is attributed to the oxidation of a primary amine precursor . 

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. 

Recently Mattingly and Miller135 have described an alkylation of /Mactam 75 as a step in the synthesis of nocardicin. 

S. Hanessian, C. Couture, and H. Wyss, Design and reactivity of organic functional groups. Utility of imidazolylsulfonates in the synthesis of monobactams and 3-amino nocardicinic acid, Can. J. Chem. (55 3613 (1985). 

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