Nocardicins synthesis

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). 

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). 

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. 

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... 

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. 

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. 

Nitrones = -V-alkylidene amine N-oxides, 153 Nitrosyl chloride diazotization with, 312-313 nitrite esters from, 286 nitrosation of enol ethers, 268 Nocardicinic acid, 3-amino- (ANA 1,1-dimethylethyl ester synthesis, 161... 

The synthesis of monocyclic 3-amino-P-lactams by the photolytic reaction of imines with pentacarbonyl[(dibenzylamino)carbene]chromium(0) was developed by Hegedus and co-workers [74]. These reactions are closely related to the previously described [2 -h 2]-cycloaddition reactions in that they are thought to involve attack of the imine nitrogen on a photogenerated, metal-bound ketene, followed by ring closure (Scheme 15). In a synthesis of a nocardicin precursor, optically active imine trimer 122 was photolyzed with carbene complex 123 providing a 46% yield of a 1 1 diastereomeric mixture of lactams... 

Several groups have shown that azetidine-2,3-diones are useful synthetic targets for the construction of p-lactams with the cephamycin [48], aspareno-mycin [49] and nocardicin [50] type side chains. Azetidine-2,3-diones like 93, have been utilized by us (Scheme 14), for the preparation of appropriately substituted P-lactam intermediates in carbapenem synthesis. 

An example of heterocycle construction via the U-4CR in the context of natural product synthesis has been demonstrated by Hofheinz and Isenring. Employing the U-4CR rapidly provided access to the functionalized p-lactam 56, which was utilized in the total synthesis of the antibiotic nocardicin A (57). In this case, marginal yields were offset by inexpensive and readily available starting materials. 

A bicyclic system can also be obtained via this method. Applications to the synthesis of /3-lactam antibiotics, such as amino-nocardicinic acid (Scheme 42) and others, have been reported. 

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... 

Further examination of the products of the organoiron reaction showed that the route was generally applicable to the synthesis of a range of pharmaceutically important P-lactam antibiotics which included thienemycin [273] (Scheme 130) and the monocyclic P-lactam systems of the nocardicins [274] (Scheme 131) and monobactams. 

Wataru Nagata, Masayuki Narisada, and Tadashi Yoshida Total Synthesis of Penicillins, Cephalosporins, and Their Nuclear Analogs Kenneth G. Holden Nocardicins... 

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. ... 

---