Efficient Macrocyclization of U-Turn Preorganized Peptidomimetics: The Role of Intramolecular H-Bond and Solvophobic Effects

Simple peptidomimetic molecules derived from amino acids were reacted with meta- and para-bis(bromomethyl)benzene in acetonitrile to very efficiently yield macrocyclic structures. The cyclization
reaction does not require high dilution techniques and seems to be insensitive to the size of the formed
macrocycle. The analysis of data obtained by 1H NMR, single-crystal X-ray diffraction, fluorescence
measurements, and molecular mechanics indicate that folded conformations can preorganize the system
for an efficient cyclization. The role played by intramolecular hydrogen-bonding and solvophobic effects in
the presence of folded conformations is analyzed.