Nocardicin derivatives

The conversion of the amide group in 34 into the carboxy group via 35 seems to be a promising way to solve the "cunide problem" of B-lactam syntheses by 4CC (refs. 2,21). The conversion of B-lactam amides into the carboxylic acids via the esters was very successful in the hands of Hofheinz and Isenring (ref. 22) who worked with the N-benzhydryl amides of nocardicin derivatives. The stereoselective and regiose-lective 1,3-dipolar cycloaddition of chiral nitrones to benzyl crotonate is a key step in our approach to thienamy-cine (ref. 23) and related carbapenam derivatives. Besides chiral 2-phenylethyl hydroxylamine (ref. 24) the 1-hydro-xylamino derivative of 2,3-5,6-diacetone mannose (ref. 25) is a promising source of chiral nitrones for such enantiose-lective cycloadditions. 

Palladium on charcoal is commonly used to promote cleavage of benzyl ether protecting groups and ultrasound was successfully used to enhance the rate of hydrogenation of the nocardicin derivative (58) [247] (Scheme 121)... 

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). 

An important group of four-membered heterocyclic compounds are the derivatives of the /i-lactam [azetidin-2-one (15)] system. Many of the compounds are biologically active, for example, the monocyclic nocardicins [e.g. (16)] and the bicyclic penicillin and cephalosporin antibiotics [e.g. (17) and (18) respectively], and the -lactamase inhibitors of the clavam group (19). 

Carbodiimides are also used in the enantioselective synthesis of 3-substituted 4-(alkoxy-carbonyl)-2-azetidinones from malic acid. DCC is used in the the synthesis of nocardicin Penam, 4-thiazabicyclo[3.2.0]heptan-7-one, and 2,3-disubstituted derivatives utilize EDCCl in the cyclization steps. ... 

In the course of studies on cyclopropanone—)5-lactam conversions, Wasserman and coworkers developed a route to the nocardicins by taking advantage of the reactivity of primary amines with cyclopropanone. The unusual susceptibility of the carbonyl group of cyclopropanone to attack by nucleophiles is well exemplified in this synthesis which involves the addition of the highly hindered malonate derivative (156) to generate the cyclopropanol adduct (157). The hindered amine (156) was previously found to be completely unreactive as a nucleophile in a displacement reaction with dibromoester (158) in an attempt to form the azetidine carboxylate (159). The further conversion of the amino malonate adduct (157) to the -lactam through a nitrenium ion rearrangement is illustrated in Scheme 59. 

In vitro and in vivo data on a tolypomycin Y derivative with Improved activity as well as the anaerobic activity of tiamulin, were published. The total syntheses of (-) vermiculine,nocardicin A, malono-micin, capreoraycin,and erythronolide B were reported. 

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). 

When vinyl halide having the amino or the hydroxyl group in a tether was treated in a similar manner, mono- or bicyclic lactams and lactones could be synthesized. This method was further extended to the synthesis of /3-lactams 21 from 2-bromoallylamine derivatives 20 (Scheme 6). ° Using this novel /3-lactam synthesis, 3-anunonocardicinic acid (3-ANA, 23), which is a core part of a monocyclic /S-lactam antibiotic, nocardicin A (22), could be synthesized from... 

Attention must be turned finally to the crucially important penicillins and cephalosporins. They, the nocardicins, e.g. nocardicin A (7.113), and clavulanic acid (7.114) have a )S-lactam ring as a common feature. [The deduced origins of (7.113) are shown [58] (7.114) derives from glycerol (3 units) and probably ketoglutarate [59].]... 

For example, nocardicin A is constructed by reacting 260 with a masked methylene imino derivative to form the [2+2] cycloadduct 261 in the key step of the synthesis ". ... 

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). 

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). 

Examination of the structure of nocardicin A (1) reveals that the compound contains three a-amino acid units and one a-oximino acid, residue and suggests that the compound is probably derived from a peptide. 

A novel synthesis of nocardicins from hexahydro-2-triazines has been reported/ The strategy behind this synthesis lies in the expectation that treatment of hexahydro-s-triazines with a Lewis acid should give formaldimines which on reaction with an acid chloride would yield monocyclic jS-lactams. This was realized in practice with the hexahydro-s-triazines derived from a-amino-acids, e.g. Scheme 95. The 3-aminonocardicin nucleus is readily available by application of the usual deprotection procedures. 

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