Further synthetic studies in penicillin C(6)-substitution including the versatile 6α-succinimidooxy leaving group

Abstract

Treatment of benzyl 6α-dimethylamino-6β-phenoxyacetamidopenicillanate 3 with methyl iodide led, in the absence of added nucleophiles, to the oxygen-bridged dimer 8via adventitious water present. Added methanol or water led to the 6α-methoxy or -hydroxy products 4 and 5; similar reactions could be performed on an α-(acytureido) penicillin.

Much more generally useful was the 6α-succinimidooxy compound 11, readily available from the 6α-methylthiopenicillin 2via metal-catalysed displacement using N-hydroxysuccinimide. This product, which was stable on prolonged storage at 0 °C, readily underwent displacement by oxygen, nitrogen, carbon and sulphur nucleophiles. Many of the products were not accessible by direct, displacement on 2 or by other methods of penicillin C(6)-substitution. The use of the even more stable 2,2,2-trichloroethoxycarbonyl protected compounds 28 and 31 permitted the introduction of biologically interesting 6β-side chains. The allyl ester series derived from intermediates 18 and 28 was important for 6α-substituents incompatible with the hydrogenolysis of benzyl esters. Final deprotection led to penicillin sodium salts 10, 25, 26, 34, 35 and 36 whose biological activities are summarised.