Exomethylene cephalosporin

Deacetoxy/deacetylcephalosporin C synthase (DAOC/DACS), the enzyme isolated from Cephalosporium acremonium catalysing587 the ring expansion of penicillin N, 473, to deacetoxycephalosporin (DAOC), 474, and the hydroxylation of 474 to deacetylcephalosporin C(DAC), 475, which in vivo is acetylated by a different enzyme to give cephalosporin C, 476 (equation 284), converts also the unnatural substrate exomethylene cephalosporin C, 477a, directly to DAC, 475 (equation 285). 

In analyzing the literature, it seemed to me that a shorter and more economical route for the conversion of II to XIV might be created if we could improve on the 25-year-old electrochemical reduction method for converting 3-acetoxymethylcephalosporins to 3-exomethylene-cephalosporins (e.g., XVI) and thence to 3-hydroxycephalosporins (XV) via ozonolysis. Shionogi s Dr. Mitsuru Yoshioka and others pointed out that many people, notably at Takeda and Eli Lilly, had published the results of their extensive efforts to achieve such an electrochemical transformation but without commercial success.29 A review of this literature quickly revealed that the major impediments to commercialization were as follows ... 

Cephems (or A -cephalosporins) can be converted into two isomers, with the double bond in the 2-position (A -cephalosporin) or 3-exomethylene cephalosporins. A convenient means of obtaining 2-... 

Cephalosporin (Ss)-sulphoxides give 2-exomethylene derivatives under Mannich reaction conditions but the corresponding (Rs)-sulphoxides fail to react530,531. 

The compounds obtained by the replacement of ring sulfur by carbon, as in the case of penicillins, show somewhat improved antibiotic properties. A free radical— based route has been described for the conversion of fermentation derived cephalosporins to their carbocyclic derivatives. The first step in this sequence consists of the condensation of the cephalosporin sulfone (36-1) with formaldehyde and dimethyla-mine the initial product from the Mannich-like reaction consists of the exomethylene derivative at the position adjacent to the activating sulfone. The product is treated in situ with phenylselenol to give the Michael adduct (36-2). This fragments with an extmsion of sulfur dioxide when heated with the free radical initiator AIBN in the presence of tributyltin hydride the reaction can be envisaged as leading to the... 

The electrochemical reduction process applied to cephalosporins gave <70% yield of desired exomethylene product, thereby introducing substantial purification problems to add to the yield losses. 

The 2-exomethylene derivatives [60] (24, 25) have opened a new route for the synthesis of further compounds, because the 2-exomethylene group can easily be transformed into other derivatives. The Mannich reaction providing (24) through the action of formaldehyde and amine salts on cephalosporin-(S)-sulphoxides is highly stereospecific no reaction has been observed in the case of cephalosporin-(R)-sulphoxides [63]. Scheme 8.1 shows the derivatives obtained from the exomethylene parent compound (24). For the bioassay results, see Tables 8.5, 8.6 and 8.7. 

This reaction, important in the synthesis of cefaclor and other cephalosporins, has been studied in detail and is discussed in Volume 1, Chapter 2. The postulated mechanism involves formation of a sulfinyl cation (88) which undergoes an ene reaction resulting in the observed product. In an alternate explanation the sulfinyl cation reacts with the double bond to give the episulfoxonium ion (89). A six-electron sigma-tropic rearrangement would then result in the observed exomethylene isomers (Scheme 3) (see Volume 1, Chapter 2). The possible intermediacy of the sulfinyl cation suggested that derivatives other than the sulfinyl chloride could be potential sources of the requisite sulfinyl cation and hence could cyclize to the exomethylenecepham sulfoxide. This has in-... 

While 3-methylenecephams themselves are completely devoid of antimicrobial activity, the exomethylene function is a distinctive feature of these compounds that many workers recognized could be a key intermediate in a chemical route to novel classes of cephalosporins with direct heteroatom substitution at C-3. Whereas 3-methylenecephams were first employed to produce deacetoxycephalosporins, exploration of their chemistry has led to the preparation of 3-chloro-3-cephems and 3-methoxyl-3-cephems that possess marked antimicrobial activity. These compounds represent a new and different generation of cephalosporin antibiotics. Two members of this class of p-lactams have achieved clinical importance. One bears the D-phenylglycyl side chain Lilly compound 99638, with the generic name cefaclor (Ceclor, Lilly). The other bears the D-cyclohexadienylglycyl side chain Ciba-Geigy Compound 9000. Both compounds are potent broad-spectrum p-lactam antibiotics with oral therapeutic efficacy. 

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