Triurea derivatives of diethylenetriamine as potential templates for the formation of artificial beta-sheets

This paper describes synthetic and structural studies of triurea derivatives of an N,N ''-disubstituted diethylenetriamine. Diethylenetriamine triureas 1 (PhN(CONHR(1))CH2CH2N(CONHR(2))CH2CH2N(CONHR(3))CH2CH2CN; 2a, R(1) = R(2) = R(3) = Ph; 2b, R(1) = R(2) = R(3) = CH3; 2c, R(1) = (S)-CH(CH(2)Ph)CO2CH3 R(2) = (S)-CH(i-Pr)CO2CH3, R(3) = (S)-CH((S)-s-Bu)CO2CH3)) are efficiently prepared in five or six steps from N-phenylethylenediamine. Infrared spectroscopy, H-1 NMR spectroscopy, and X-ray crystallography indicate that triureas 1 adopt intramolecularly hydrogen-bonded conformations, both in chloroform solution and in the solid state. The three urea groups form a hydrogen-bonded network: The carbonyl group of urea NCONHR(1) is hydrogen bonded to the NH group of urea NCONHR(2), and the carbonyl group of urea NCONHR(2) is hydrogen bonded to the NH group of urea NCONHR(3). The three R groups are aligned along the triurea backbone, pointing in roughly the same direction, like three fingers on a hand. Molecular modeling suggests that the triurea backbone will be a suitable template for the creation of artificial beta-sheets. When molecular mechanics energy minimization calculations are performed upon a triurea bearing three N-terminally linked peptide strands, a parallel beta-sheet is formed.