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Triurea Derivatives of Diethylenetriamine as Potential Templates for the Formation of Artificial β-Sheets1

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posted on 07.02.1996, 00:00 by James S. Nowick, Sami Mahrus, Eric M. Smith, Joseph W. Ziller
This paper describes synthetic and structural studies of triurea derivatives of an N,N"-disubstituted diethylenetriamine. Diethylenetriamine triureas 1 (PhN(CONHR1)CH2CH2N(CONHR2)CH2CH2N(CONHR3)CH2CH2CN; 2a, R1 = R2 = R3 = Ph; 2b, R1 = R2 = R3 = CH3; 2c, R1 = (S)-CH(CH2Ph)CO2CH3, R2 = (S)-CH(i-Pr)CO2CH3, R3 = (S)-CH((S)-s-Bu)CO2CH3)) are efficiently prepared in five or six steps from N-phenylethylenediamine. Infrared spectroscopy, 1H 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 NCONHR1 is hydrogen bonded to the NH group of urea NCONHR2, and the carbonyl group of urea NCONHR2 is hydrogen bonded to the NH group of urea NCONHR3. 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 β-sheets. When molecular mechanics energy minimization calculations are performed upon a triurea bearing three N-terminally linked peptide strands, a parallel β-sheet is formed.