Epimerization Induced by a Remote Cationic Center in Potent New Carbapenems

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A new, potent 1β-methylcarbapenem (FR21751) containing a novel pyridiniomethylpyrrolidine side chain has been synthesized, and was found to undergo epimerization at the pyrrolidine C-2 position. To investigate this isomerization, we evaluated the epimerization rate by HPLC at various pH values in aqueous solution and the deuterium exchange rate by ^1H-NMR spectroscopy in buffered D_2O solution. The rate of this epimerization was greater at high pH (≧6), and deuterium exchange occurred only at the benzylic position of the pyridine ring. The results can be interpreted in terms of a mechanism involving anionic and acyclic intermediates. We synthesized the postulated acyclic intermediate of this epimerization independently and demonstrated its cyclization to give a mixture of four diastereomers (6a, 9), in support of our proposed mechanism.
公益社団法人日本薬学会の論文
1997-01-15