Penam product formation

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).

The structure of the penam product denounces migration of a phenylthio group, which requires the involvement of dipolar species 320 in the C2-C3 bond formation. This intermediate would arise from the 3-thiacepham sulfonium ylide 319, which is a reasonable product of intramolecular carbene trapping (318 - 319) by the thioether sulfur atom, in the absence of the thioxo sulfur atom. Thus, three different 3-thiacepham dipolar species (313,314,319) formally participate in as many penem ring formation strategies. This is one of the fascinating aspects of P-lactam chemistry. 

We were surprised to find that despite the general lability of penam derivatives, the products (154) could be purified by sublimation in vacuo. Using a similar scheme, Sjoberg synthesized the amide of a stereoisomer of penicillin G, but in very low overall yield, because formation of the required 3-thiazoline derivative by the Asinger condensation did not proceed satisfactorily. 

Similarly, in the case of determination of penam analysis during acidic hydrolysis (1.0 M HCl), formation of non-absorbing degradation products was the intermediate stage of their analysis. Complex which is necessary for achievement of spectrophotometric signals, was formed between penicillamine and palladium(ll) chloride, peak at 334 nm (Fig. 18) [58]. 

Other C2-C3 bond formation strategies for the preparation of penam compounds susceptible to elimination to penems are represented overleaf. Route A has found application in carbapenem synthesis [Aldol-type approach 178] but failed on substrate 300, probably owing to mercaptide expulsion [29b]. Route B failed as well [29b], since the expected product, 303, would undergo retro-aldol reaction to the starting material 302 [84b]. If this possibility is precluded, as in... 

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