EPIMERIZATION INDUCED BY A REMOTE CATIONIC CENTER IN POTENT NEW CARBAPENEMS

A new, potent 1 beta-methylcarbapenem (FR21751) containing a novel pyr idiniomethylpyrrolidine side chain has been synthesized, and was found to undergo epimerization at the pyrrolidine C-2 position. To investig ate this isomerization, we evaluated the epimerization rate by HPLC at various pH values in aqueous solution and the deuterium exchange rate by H-1-NMR spectroscopy in buffered D2O solution. The rate of this ep imerization was greater at high pH (greater than or equal to 6), and d euterium exchange occurred only at the benzylic position of the pyridi ne ring. The results can be interpreted in terms of a mechanism involv ing anionic and acyclic intermediates, We synthesized the postulated a cyclic intermediate of this epimerization independently and demonstrat ed its cyclization to give a mixture of four diastereomers (6a, 9), in support of our proposed mechanism.