Cepham 3-methylene

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). 

Experiments on cephalosporin C biosynthesis using these precursors were less conclusive as mass spectrometric analysis seemed to be eomplicated by deuterium scrambling in the spectrometer. It appeared that although two deuterium atoms were located on the exocyclic methylene group in cephalosporin C derived from (225), perhaps one (rather than two) was located at C-2 in material arising from the C-3 epimer. N.m.r. spectroscopy, however, indicated within the limits of measurement that two deuterium atoms were present at C-2. Further, no deuterium was incorporated into cephalosporin C produced microbially in deuterium oxide. It is thus probable that incorporation of the C-3 epimer of (225) is with retention of two deuterium atoms and it follows that formation of the A -cepham nucleus does not proceed via a A -cepham intermediate. On the other hand the results are in accord with intermediacy of compounds like (224). 

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... 

Methylene cephams (360) have been prepared in yields of about 60% by the photocyclization of the disulphide (359) in acetonitrile using a high-pressure mercury lamp. ... 

The synthesis of a methylene cepham by cyclization of an allylic halide has been described by the Lilly group. Reaction of the chloride (361) with potassium iodide in acetone gave a 50% yield of (362). 

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