Penicillin acylimine

After formation of the acylimine (12), methanol adds to the less sterically hindered a-face of the molecule with high selectivity to provide (13). A further direct incorporation of a 6a-methoxy group (41) and subsequendy a 6a-formamido group into penicillin has been achieved using ttiduoromethanesulfonamides of type (14) (42). 

Firestone and Christensen (1973) employed phenyllithium rather than lithium methoxide to achieve direct introduction. Penicillin G benzyl ester (81), when reacted with phenyllithium in THF at -78 C, followed by /ert-butyl hypochlorite and finally quenched with methanol, gave 6a-methoxypenicillin G benzyl ester (82). Analogously, quenching of the acylimine intermediate with water or triethylammonium formate gave 83 and 84, respectively. Hydrogenolysis of these materials was achieved with 10% Pd-C, NaHCOj, and methanol-water, at 40 psi. The resulting sodium salts exhibited markedly lower antimicrobial activity than 37. A major by-product always formed in these conversions was assigned structure 85. 

Hypochlorite oxidation of suitable penicillin derivatives has allowed a more direct route to 6a-methoxypenicillins. Thus N-chlorina-tion-dehydrochlorination of the penicillin sulphoxide (27 b, y) in a borate buffer generated the acylimine (29 y, = PhOCHj) uio the N-chloro-amide... 

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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