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 be en studied. MMX calculations predicted, and 2D NOESY confirmed, that the be nt conformation (global energy minimum) was such that six-membered ring for mation, and not macrocyclization, would occur using the corresponding nitre nium ion, and this was found to be the case. Acid-catalyzed decomposition o f 1-(3-benzyloxyphenyl)-2-(4-azidophenyl)ethane followed by treatment with (CF3CO)(2)O gave 48% of 2-benzyloxy-6-trifluoroacetamido-9,10-dihydrophenan threne and 18% of 1-(3-benzyloxyphenyl)-2-(4-trifluoroacetamidophenyl)ethan e. Blocking the original point of attack with a bromine atom led to the pre diction (MMX, 2D NOESY) that, once again, small ring formation would take p lace, 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 accessi ble conformation that could result in intramolecular cyclization leading to macrocycles being preferred over intermolecular reactions.