Cepham sulfoxides

Ozonolysis has also been demonstrated to play a role in the production of another important intermediate in (3-lactam synthesis, hydroxyl-cepham sulfoxide esters 92.84 Ozonolysis plays a role in the conversion of a methylene group in compound 93 into the required hydroxy group in compound 92 (Scheme 11.25). 

The ADEPT approach has been recently investigated as a means of overcoming the side-effects of using taxol to treat breast cancer by utilizing a /Mactamasc enzyme antitumor antibody conjugate and a cepham sulfoxide derivative of taxol (PROTAX). The localized /Mactamase enzyme, which is not normally found in any other tissues, ensures selective release of taxol at the tumor site. The prodrag is almost as effective as... 

Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

Morin et al. showed that the reaction of penicillin sulfoxides (162) with refluxing acetic anhydride leads to formation of the ring-expanded cepham derivatives (165) and compound (166 Scheme 41). Although this transformation was effected under Pummerer conditions, it occurs by a different mechanism, hence the term Abnormal Pummerer reaction . 

Disubstituted penams 7,7-disubstituted cephams. Reaction of the penicillanate ester (2) with (1) results in incorporation of the urethane group at Cft to give (3) in high yield. The penam (3) can be converted into the cepham (5) by way of the sulfoxide (4). 

Use of an acyl halide (Tanida et al., 1975a) (e.g., benzoyl chloride and pyridine in refluxing toluene) resulted in a different product, the 2 -chloromethylpenem (71), in respectable yield. The phthalimidopenicillin sulfoxide (30) gave the two isomers 72 and 73 in approximately equal amounts. On further heating in a dipolar aprotic solvent, 72 rearranged to the cepham 74 from which the elimination of hydrogen chloride resulted in formation of the A -deacetoxycephem (75). 

A utility for this reaction was demonstrated by the reaction of the penicillin sulfoxide hydrazide derivative (143) with 2-propoxypropene to afford the enol ether (144). This was then hydrolyzed with mercuric nitrate to afford the ketone (145) (Ager et al., 1973). Ozonolysis of 145 gave the diketone (146) which on treatment with base cyclized to cepham... 

The stereochemistry at C-4 in 3-methylenecephams derived from these chemical reductions was determined from detailed NMR studies on their sulfoxides and computer calculations based on lanthanide-induced NMR shifts (Ochiai et ai, 1972d,e). Both procedures led to the conclusion that the proton at position 4 was in the p orientation. Methyl 7-phenoxyace-tamido-3-methylene-cepham-4-carboxylate (16) was oxidized with m-chloroperbenzoic acid to give the p-sulfoxide (17S), and with N,N-di-chlorourethane to give the a-sulfoxide (17R). The anisotropic effect of each sulfoxide on its respective C-4 proton was examined. The proton at C-4 was found to be shielded by 0.06 ppm in the a-sulfoxide (R) and deshielded by 0.09 ppm in the p-sulfoxide (5). Dreiding models of the two conformational possibilities (A) and (B) for both sulfoxides suggest... 

A more recent synthesis of 3-methylenecephams from cephalosporins utilizes mercury salts in a metal-assisted reaction with 3-methyl-3-hal-ocepham ester sulfoxides. Although ordinarily dehydrohalogenations of 3-halo-3-methylcephams lead to the thermodynamically more stable 3-methyl-2-cephems and -3-cephems, chemists at Dista Products Limited (England) discovered that electrophilic mercury salts specifically led to 3-methylenecephams (Corfield and Taylor, 1978). When p-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-bromo(or 3-iodo)cepham-4-carboxylate 1-oxide (47) was treated with mercury(I or II) perchlorate in dimethox-yethane for 18 hr at room temperature, p-nitrobenzyl 7-phenoxyacetam-ido-3-methylenecepham-4-carboxylate 1-oxide (48) was obtained in 75% yield. No other metal salt (in a variety of solvents) effected this transformation. Their view of the mechanism of this reaction is detailed later in this chapter. 

Deuterium-labeled phenylmethylpenicillin sulfoxide trichloroethyl ester (98) was reacted with thiodeuterated 2-mercaptobenzothiazole (99) to give disulfide 100 which upon irradiation afforded a 2 1 mixture of cephams 101 and 102 with deuterium only at C-2. This experiment again... 

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