Conformational and steric modifications of the pyran ring of the potassium-channel activator cromakalim

Abstract

The syntheses of analogues of the novel smooth muscle relaxant cromakalim, in which the C-2 methyl groups have been successively replaced by hydrogen, are described and the relative stereochemistry of the two corresponding, isomeric monomethyl compounds, unambiguously assigned by ¹H NMR spectroscopic techniques. Single-crystal X-ray analysis of the 2α-monomethyl compound showed that it existed in a distorted half-chair conformation in the solid state and confirmed the relative orientation of the C-2, C-3 and C-4 substituents. The 2β-Me isomer appeared to exist in a single conformation in solution, with the pyran ring adopting a half-chair conformation and with all the substituents in this ring occupying a pseudoequatorial position. The solution behaviour of the 2α-Me isomer is more complex, however, although it seems likely to exist as a distorted half-chair conformer similar to that found in the solid state. The syntheses of two related benzoxepines are also described. All compounds were less potent than cromakalim itself, which is consistent with the view that dimethyl substitution at C-2 is essential for optimal activity.