Structural modifications of the potassium channel activator cromakalim: the C-3 position

Abstract

The syntheses of a selection of C-3 analogues of 6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-2H-1-benzopyran-3-ol, the potassium channel activator cromakalim 1, are described. Particular interest has focused on the corresponding 3-ketone 2 and compounds in which the hydroxy group of 1 has been replaced by fluorine, carbon and nitrogen containing residues. The hindered neopentylic nature of the C-3 hydroxy group in 1 has a marked effect on its reactivity and has necessitated the independent synthesis of many of these analogues from simpler precursors rather than from the direct modification of compound 1 itself.