Of nocardicine

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

The target molecule ethyl a-[p-(benzyloxy)phenyl]-2-oxo-l-azetidineacetate (20) (Expt 8.7) is an intermediate in the synthesis of one of the compounds of nocardicin group.12 It is an interesting example with which to illustrate the application of retrosynthetic analysis in this field. 

In a similar vein, Ugi and co-workers have also prepared carbapenems and cephalosporin analogues. Maintaining the same tethering relationship, several hundred /Mactam analogues of nocardicin were also reported by Hofheinz and coworkers in 1981 (Scheme 11.14) [66]. Nocardicin A 70 (Scheme 11.14) isolated in... 

Tritium at C-2 of either (110) or its D-isomer was lost on formation of (113), and the L-isomer (110) was the preferred precursor of nocardicin. These results parallel those for the utilization of valine in the biosynthesis of penicillins, and it has been suggested that the configurational inversion of L-(/ -hydroxyphenyl)glycine (110) which necessarily occurs in the course of the biosynthesis of nocardicin may also parallel the inversion of L-valine which occurs in the biosynthesis of penicillins (cf. above). 

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. ... 

A recent synthesis of 3-aminonocardicinic acid (3, the nucleus of nocardicins, antibiotics from actinomycetes) involved this cyclization of a /3-halopropionamide. Thus treatment of 1 with NaH in dilute solution (DMF-CH2CI2) led to the /3-lactam... 

The nocardicins (135) are monocyclic 3-lactam antibiotics. The essential step in the synthesis of the nocardicins by Isenring and Hofheinz is the formation of (139) from (S)-isoserine (136) by 4CC. Their synthesis of isonocardicin A, a diastereomer of (135a) from (S)-homoserine follows the same pattern, as well as the preparation of numerous analogs of nocardicin. 

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. 

An example of 0-amino-carboxy-propylation is provided by the biosynthesis of nocardicin A (p-lactam antibiotic produced by the actinomyceteNocarafia uniformis) (Section 4.1.5) (Figure 1.8). 

The nocardicins are a family of monocyclic BLAs produced by the actinomycete Nocardia uniformis subsp. tsuyamanensis ATCC 21806, first isolated in 1976. Nocardicin A is the major product, with several other structurally related metabolites in smaller amounts, nocardicins B-G (Figure 4.14). Nocardicin A was the first member of this family to be reported [52]. In the same year, the isolation of nocardicin B was also reported [53]. The structures 29 and 30 were soon assigned to nocardicin A and B, respectively [54,55]. One year later, the isolation of nocardicins C-G was reported, and the assignment of the structures 31-35 were proposed in the same paper [56]. Nocardicin A has also been isolated from the actinomycetes Actinosynnema mirum [57], Nocardiopsis atra [58], and Microtetraspora caesia [59]. The nocardicins were the first naturally occurring monocyclic p-lactams that display any significant antibacterial activity to be isolated, and they bear structural... 

Figure 4.15 Amino acid origin and biosynthetic pathway of nocardicins.

Total syntheses of nocardicin A and D have been reported. The important stage is the preparation of 3-aminonocardicinic acid from 4-hydroxyphenylglycine via an acid chloride-imine reaction (Scheme 128). ... 

The first report of a specific screening technique designed to search for p-lactam antibiotic-producing cultures was described by Kitano et al. (1975). A mutant of Pseudomonas aeruginosa highly and specifically sensitive to p-lactam antibiotics was isolated. A similar mutant strain of Escherichia coli highly sensitive to p-lactam antibiotics was used in the detection of nocardicins (Aoki et al., 1976). 

As has been stated above, reaction of n-allyl tricarbonyliron lactone complexes with amines in the presence of Lewis acids such as ZnQ2 results in the formation of the corresponding tricarbonyliron lactam complexes via an Sn2 reaction. These complexes (e.g. 46) may be converted by CAN to p-lac-tams such as 44 (Scheme 4.15) in an exactly analogous way to the method described above. Since p-lactams occur in numerous physiologically important natural products this is a valuable reaction sequence which has been applied to the synthesis of nocardicins and thienamydn. Recently a synthesis of pyrrolizidine alkaloids has been developed using this methodology. ... 

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). 

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. 

The first reported study on the biosynthesis of nocardicin A was by Hosoda etal, who administered a variety of C-labelled compounds to shaken fermentations of Nocardia miformis subsp. tsuyamonensis 206). Examination of the resulting nocardicin A showed that L-[U- C]-tyrosine, [G- CJ-shikimic acid, and L-[U- C]-serine were all incorporated into the antibiotic. [U- C]-Glycine and L-[U- C]-homoserine were also incorporated but to a lesser degree, whereas the labels from L-[l- C]-tyrosine, L-[U- C]-phenylalanine, L-[U- C]-alanine and DL-[U- C]-a-amino-butyric acid were not incorporated to any significant extent. 

By use of the above degradations the authors showed that L-[U- C]-tyrosine was incorporated specifically into the two aromatic residues, L-[U- C]-homoserine was incorporated specifically into the D-homo-serinyl residue and L-[U- C]-serine was incorporated specifically into the p-lactam ring of nocardicin A. 

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