Acetogenic isoquinoline alkaloids, XXI. An atropisomer-differentiating reaction for the chemical analysis of axial chirality and its computational investigation: Proof of the stereostructure of dioncophylline A†

A chemical method for the unambiguous elucidation of axial chirality in naphthylisoquinoline alkaloids such as dioncophylline A (1a) is described. It involves synthetic connection of the stereogenic axis to be investigated with the stereocenters present in the same molecule. The resulting macrocyclic ansa compound 7c is formed in high yield, yet exclusively for only one of the two atropodiastereomers (4c), the other isomer (4b) does not cyclize at all. This cyclization behavior fully confirms the stereostructure 1a of dioncophylline A, as postulated by us earlier. For an interpretation of the striking atropisomer specificity of this ring closure reaction, computer-assisted theoretical investigations on the molecular geometries and thus thermodynamical properties of both of the imaginable cyclization products 7b/c have been performed by using force-field (MM2, MMX) and semiempirical methods (AM1). The optimized structures show the obtained macrocycle 7c to be a nonstrained, stable compound, whereas the other possible product 7b (which definitely is not formed) should be severely distorted.