Penicillin synthetic

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). 

Many semi-synthetic penicillins are made from 6-aminopenicillanic acid (6-APA, R = NH2>. 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporkis, a number of which are synthesized by acylation of fermentation-derived 7-amkiocephalosporanic acid, are an example. Two orally active cephalosporkis called cefroxadine and cephalexin are produced by a synthetic ring-expansion of penicillin V. 

The development of new antibiotics to combat resistance, and to provide easier oral administration and improved pharmacokinetics has been successful through synthetic modifications. This approach has been particularly rewarding in the area of P-lactams. The commercial importance of the P-lactams is evident from Table 3 which gives the market share of antibacterials. Fully 62% of the 1989 world antibacterial market belonged to the cephalosporin and penicillin P-lactams (20). 

In the period up to 1970 most P-lactam research was concerned with the penicillin and cephalosporin group of antibiotics (1). Since that time, however, a wide variety of new mono- and bicychc P-lactam stmctures have been described. The carbapenems, characterized by the presence of the bicychc ting systems (1, X = CH2) originated from natural sources the penem ring (1, X = S) and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are 7-oxo-(R)-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxyhc acid [78854-41-8] CyH NO, and 7-oxo-(R)-4-thia-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxylic a.cid [69126-94-9], C H NO S, respectively. 

Chemical Modification. The chemistry and synthetic strategies used in the commercial synthesis of cephalosporins have been reviewed (87) and can be broadly divided into ( /) Selection of starting material penicillin precursors must be rearranged to the cephalosporin nucleus (2) cleavage of the acyl side chain of the precursor (2) synthesis of the C-7 and C-3 side-chain precursors (4) acylation of the C-7 amino function to introduce the desked acylamino side chain (5) kitroduction of the C-3 substituent and 6) protection and/or activation of functional groups that may be requked. 

As many natural and synthetic /3-lactams bear 3-acylamino substituents, the corresponding free amines or protected forms thereof are versatile synthetic intermediates. They may be prepared in several ways, for example by deacylation of the 7-amido group in naturally occurring penicillins by enzymic or chemical means. Chemical degradation usually involves conversion of the amide to a chloroimidate followed by cleavage with aqueous alcohols (75S547 p. 560, 78T1731 p. 1753). 

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). 

Another synthetic sequence leading to penicillin derivatives is illustrated in Scheme 61 (77MI51102). Note that the cycloaddition of azidoacetyl chloride to the thiazoline affords an azidopenam with the 6-epi configuration. Equilibration leads to a mixture of (81) and (82) in a ratio of 4 1, but repeated recycling allowed the isolation of (82) in 40% yield. A related synthesis was shown in Scheme 26. 

In contrast to the preceding synthetic routes, the sequence shown in Scheme 62 forms the /3-lactam ring before closing the thiazolidine ring (80JCS(P1)2228 and refs, therein). The product (83) had been previously reported and converted to the corresponding penicillin derivative (see Scheme 61) (77MI51102). 

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... 

Sheehan s concentrated attack upon the penicillin synthesis problem began in 1948 and was conducted on a broad front. It was anticipated at the outset that the formidable penicillin V molecule would succumb to organic synthesis only in the event that new powerful and selective methods of organic synthesis are brought to bear on the problem. But, in addition, and perhaps more importantly, these new synthetic methods must be mild enough to contend with... 

Figure 6.14 Enzymatic side chain cleavage of penicillins. 6-Aminopenicillanic acid, a valuable intermediate for the production of various semi-synthetic penicillins, can be obtained through enzyme-mediated hydrolysis of the phenylacety group of penicillin G or the phenoxyacetyl group of penicillin V. The active site of the enzyme recognises the aromatic side chain and the amide linkage, rather than the penidllin nucleus. Chemical entitles other than penicillins are therefore often good substrates, as long as they contain the aromatic acetamide moiety.

Before we leave our discussion of preparing 6-aminopenicillanic acid for use as a starting material in the manufacture of semi-synthetic penicillins, we should point out that similar processes are used in the manufacture of semi-synthetic cephalosporins. Here tire key intermediate is 7-aminodeacetoxycephalosporanic add (7-ADCA). We have drawn outline schemes comparing the production of semi-synthetic penicillins and cephalosporins in Figure 6.15. You will see that the two schemes are very similar. 

Figure 6.15 Production of semi-synthetic penicillins (left) and cephalosporins (right), from enzymatically obtained intermediates 6-APA and 7-ADCA respectively.

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