Intramolecular cyclizations via arylnitrenium ions. Formation of a six-membered ring rather than a macrocycle

The stereochemistry of 1-(3-benzyloxyphenyl)-2-(4-nitrophenyl)ethane has been studied. MMX calculations predicted, and 2D NOESY confirmed, that the bent conformation (global energy minimum) was such that six-membered ring formation, and not macrocyclization, would occur using the corresponding nitrenium ion, and this was found to be the case. Acid-catalyzed decomposition of 1-(3-benzyloxyphenyl)-2-(4-azidophenyl)ethane followed by treatment with (CF3CO)(2)O gave 48% of 2-benzyloxy-6-trifluoroacetamido-9,10-dihydrophenanthrene and 18% of 1-(3-benzyloxyphenyl)-2-(4-trifluoroacetamidophenyl)ethane. Blocking the original point of attack with a bromine atom led to the prediction (MMX, 2D NOESY) that, once again, small ring formation would take place, with macrocyclization possible but less likely. Again, this was found to be so. It is suggested that simple MMX calculations may provide a very rapid, empirical indicator of which precursors would have a readily accessible conformation that could result in intramolecular cyclization leading to macrocycles being preferred over intermolecular reactions.