Cephalosporins sulphoxides

The deoxygenation of some penicillin and cephalosporin sulphoxides has been accomplished by the use of phosphorus pentasulphide.53 The reactive species responsible for deoxygenation was not identified. A particularly mild method for reducing sulphoxides to sulphides involves the reaction of the sulphoxide with 2-chloro-l,3,2-benzodioxaphosphole at room temperature.536 Yields in excess of 80% were reported. 

In the cephalosporin sulphoxides the 2-methylene group contains moderately labile protons. The 2-methylene group has some allylic character, but the 2-halogeno derivatives can not be obtained from the A -sulphides however, the corresponding sulphoxides do undergo this... 

Cleavage of the 1,2-bond has also been achieved by chlorination or bromin-ation of penicillin sulphoxides. The resulting sulphinyl bromide (103 y) or chloride (104 t) cyclizes readily to the A -cephalosporin sulphoxide (2 X = H). The reaction of (103 t) with diazomethane, however, gives a mixture of three novel cepham sulphoxides (105 t), (106 t), and (107 t) as well as the chloromethyl sulphoxide (109 t). These products are believed to result from a diazo-sul-phoxide (108 t), which undergoes a rapid intramolecular cyclization, via either the sulphoxocarbene (110) or the pyrazoline (111). Cephalosporins (112) and (113), derived from these sulphoxides, exhibited weak antibacterial activity. 

The first general method of transforming a penicillin into a cephalosporin, the acid-catalysed rearrangement of penicillin sulphoxides, continues to receive attention. That this rearrangement proceeds via a sulphenic acid derivative has been further confirmed by isolation of the crystalline sulphenic acid (74 f, y) from the thermal rearrangement of the penicillin sulphoxide (27 f, y). This intermediate slowly reverts to the penicillin at 38 0, and, on treatment with methanesulphonic acid in dimethylacetamide, cyclizes to cephalosporin (75 f, y). Trapping of (74) by oxidation to the sulphinyl chloride (76 f, y) has been reported cyclization to a cephalosporin sulphoxide was accomplished under base catalysis/ Treatment of penicillin sulphoxides with azo-compounds also effects rearrangement to... 

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

In the presence of oxidizing agents (e.g. sodium metaperiodate, hydrogen peroxide, m-chloroperbenzoic acid, t-butyl-hypochlorite, iodobenzene dichloride, etc.) both penicillins and cephalosporins undergo facile oxidation to either sulphoxides or sulphones. The esters of penicillin sulphox-ides (4) were described in 1949 [1]. It was found later [5] that the free acids could be oxidized by periodate. When a 6(7)-/3-acylamino side-chain is present in the molecule the resulting reagent-approach control due to the N-H proton promotes the formation of the (S)-sulphoxide (4a) [6,7]. 

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. 

In 1948, Brotzu reported on the biological activity of a crude extract from a Cephalosporium sp. that subsequently led to the identification in the late 1950s of another -lactam series, the basis for which was cephalosporin C (19a). Very soon after the identification of this molecule, workers at Lilly were able to convert methyl penicillin V via its sulphoxide into a cephalosporin. Further work then led to... 

An important industrial process using peracetic acid for sulphoxide formation is that of 7-ADCA (7-aminodeacetoxycephalosporanic acid, a cephalosporin antibiotic precursor) production, in which penicillin is oxidised to sulphoxide followed by ring-expansion [218] (Figure 9.11). 

From Penicillins (Type C). The important problem of the relationship between penicillin, cephalosporin, and isothiazole derivatives has recently interested several research groups. This topic is also considered in Chapter 16. The anion of azetidinesulphenic acid (20) undergoes spontaneous fragmentation and re-cyclization, giving the isothiazolone derivative (21) in high yield. Direct treatment of penicillin sulphoxides with bases has previously given isothiazoles similarly, and further examples continue to be reported. The 4-mercapto-... 

Modification at C-2 of the cephalosporin skeleton has attracted limited interest, since those transformations which have been reported have not led to products with significantly improved antibiotic properties. Low-temperature methyl-thiolation of cephem sulphoxide (58) via its C-2 anion afforded thiomethyl derivative (59). The reaction proceeded stereospecifically from the least hindered side to give the a-isomer exclusively. When the reaction was carried out at a somewhat higher temperature (- 23 °C), the bis(methylthio)-compound... 

Structural modifications at C-4 of the cephalosporins have received limited attention. Methylthiolation at C-4 was observed when the sulphoxide (58) was treated either with MeSS02Me or MeSOCl. The )S-methylthio-isomer (79) is... 

Bond Cleavage.—The thermal or acid-catalysed rearrangement of penicillin (S-oxides to cephalosporins has been shown to proceed through a reactive sulphenic acid (80 y), which may be isolated in crystalline form in low yield. This intermediate slowly reverts on standing to the starting sulphoxide, while under acid... 

A similar penicillin sulphoxide-cephalosporin transformation, initiated with acetyl chloride-pyridine, has also been described. The disulphide (93 b) and sulphenanilide (94 b) have been prepared from the sulphenic acid (80). These sulphenyl derivatives readily cyclize to penicillins (95 b) and cephems (96 b). 

Hydrolysis of cephalosporin / -nitrobenzyl esters by microbial enzymes has been described. A convenient high-yield method for preparing benzhydryl esters of penicillins and cephalosporins has been described. Diphenyl-diazomethane is generated in situ in the presence of the antibiotic by oxidation with peroxyacetic acid of benzophenone hydrazone. Diazomethane has been found to add to 3-methyl-A -cephem sulphides, sulphoxides, and sulphones preferentially from the j3-side to give the respective pyrazolino-cephams (194 b). ... 

The isothiazolone (68) undergoes base-catalysed rearrangement in di-methyl-acetamide or -formamide, yielding (70), presumably by way of the intermediate acylimine (69). The observation is of significance in penicillin chemistry, since compounds (68) and (70), amongst others, are by-products of the transformation of penicillin V sulphoxide methyl esters into cephalosporin derivatives/ ... 

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