Cephalosporin total synthesis

Early attempts to apply the Sheehan penicillin synthetic strategy to the total synthesis of cephalosporins were not particularly successful. Although the key step, formation of the /3-lactam CO—N bond, could be carried out efficiently (46->47), subsequent conversion of the lactone to a free C-4 carboxyl could only be accomplished in poor yield (B-72MI51007). 

Woodward s total synthesis of cephalosporin C begins with L-cysteine (48) which establishes the chiral center at C-7. The cis geometry at C-6,7 is achieved in intermediate (49) which is cyclized to (50) by treatment with triethylaluminum. The dihydrothiazine ring is constructed by Michael addition to the condensation product of trichloroethyl glyoxylate... 

In spite of the considerable progress in developing methods for total synthesis, this route to cephalosporins cannot compete with fermentation or penicillin rearrangement (see Sections 5.10.4.1 and 2) for the industrial production of cephalosporin antibiotics. While total synthesis does provide access to nuclear analogs not readily obtainable from fermentation products, none of the totally synthetic materials have displayed sufficient advantages to Warrant their development as new drug products (b-81MI51000). 

Cephalosporanic acid, 3 -deacetoxy-, 7, 289 Cephalosporin, 3 -deacetoxy-absorption, 7, 293 synthesis, 7, 293 Cephalosporin, 3,4-dihydro-synthesis, 7, 292 Cephalosporin, 7a-hydroxy-synthesis, 7, 290 Cephalosporin C, 7, 288 as pharmaceutical, 1, 152 total synthesis, 7, 294 Woodward s total synthesis, 7, 294 Cephalosporin C, deacetoxy-synthesis, 7, 292 Cephalosporins, 7, 267, 285-298 7-acylamino substituent configuration, 7, 290 analogues synthesis, 7, 288 as antibiotics, 2, 519 3, 1038 application, 7, 296... 

The total syntheses of penicillin and cephalosporin represent elegant tours de force that demonstrated once again the power of synthetic organic chemistry. These syntheses, however, had little effect on the course of drug development in the respective fields, since they failed to provide access to analogs that could not be prepared by modification of either the side chains or, as in the case of more recent work, modification of 6-APA and 7-ACA themselves. In order to have an impact on drug development, a total synthesis must provide means for preparing... 

Holden, K. G., Total Synthesis of Penicillins, Cephalosporins and Their Nuclear Analogs in Chemistry and Biology of p-Lactam Antibiotics, Morin, R. B. Gorman, M., Eds. Academic Press New York, 1982 Vol. 2, pp. 99-164. 

A classical example in which an intensive and systematic application of all the auxiliary physical techniques -including X-ray diffraction analysis- was made, is provided by the total synthesis of cephalosporine C by Woodward and coworkers [30]. However, in order to illustrate this important principle, we will consider a much more simple example, that is already familiar to us. Let us consider the synthesis of patulin as originally planned in our laboratory (see above 3 1). 

The total synthesis of penicillin V was achieved by J. C. Sheehan (1957) and of cephalosporin by R. B. Woodward (1966). Biosynthetic routes have been worked out in part, and the precursors to both ring systems are L-cysteine and D-valine ... 

To date, the number of penicillin and cephalosporin-based molecules produced by semi- and total synthesis is well in excess of 20000. Most started with modification of the fermentation product, 6-amino-penicillanic acid 20 or the corresponding cephalosporin, 7-amino-cephalosporanic acid 21, both of which can be produced by simple chemical or biochemical deacylation from penicillin or cephalosporin C. The number above is only approximate as a significant proportion of structures from industry were never formally published, or were only mentioned in the patent literature—particularly if they had marginal or no significant activity levels over those which had been reported previously. 

For complexes of type 10 (with a hydrogen at the carbene carbon) a synthesis was worked out in which a formamide is first reacted with K2[Cr(CO)j] followed by reaction with TMSCI [7]. This way, the non-racemic formamide 12 leads to the chirally modified amino carbene complex 13, which serves as starting material for the diastereoselective synthesis of various optically active yff-lactams [8]. An example is the (formal) total synthesis of 1-carbacephalothin 16, a carbon analog of the cephalosporins (Scheme 5) [8b]. In this case, the complex 13 is irradiated in the presence of in situ prepared imine 14 to afford the /(-lactam with high dia-stereoselectivity but only in modest yield. The product (15) could (in principle) be converted in to the target compound 16. 

On the basis of the work of CIBA-Geigy A. G. and the Woodward Forschungsinstitut, the original total synthesis of cephalosporin has been extended with the incorporation of many fascinating details to the preparation of new derivatives [64-73]. Some features of this extensive work are shown in Scheme 8.2. Although an analysis of antibiotic activities toward different strains has not been published so far, it was found that (39) ( Cephalocillin ) and (40) are able to inhibit S. aureus, Proteus vulgaris and Bacillus megaterium [26]. 

The peneras were conceived by R.B. Woodward in 1976 as structural hybrids of penicillins and cephalosporins [84]. Unlike the carbapenems and clavams, they are not found in nature. They do however possess important biological properties and have therefore created considerable interest in both their total synthesis and their biological evaluation [85]. 

The crowning intellectual achievement of the year was Woodward s S brilliant total synthesis of cephalothin (X) and cephalosporin C (XIII) via a key intermediate presumably useful for the synthesis of unique variants of both cephalosporins and penicillins. 

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