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

• Published in: Journal of the American Chemical Society Vol. 125; no. 22; pp. 6677 - 6686
• Main Authors: Becerril, Jorge, Bolte, Michael, Burguete, M. Isabel, Galindo, Francisco, García-España, Enrique, Luis, Santiago V, Miravet, Juan F
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.06.2003; Amer Chemical Soc
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amino Acids - chemistry; Biomimetic Materials - chemistry; Chemistry; Chemistry, Multidisciplinary; Computer Simulation; Cyclization; Exact sciences and technology; Hydrogen Bonding; Kinetics and mechanisms; Magnetic Resonance Spectroscopy; Models, Molecular; Organic chemistry; Peptides - chemistry; Physical Sciences; Protein Folding; Reactivity and mechanisms; Science & Technology; Solvents; Spectrometry, Fluorescence; Toluene - analogs & derivatives; X-Ray Diffraction; CATALYSIS; DESIGN; LIGANDS; RECOGNITION; AMINO-ACIDS; CONFORMATION; INHIBITORS; RECEPTORS; LARGER; PEPTIDE; Solvent effect; Monte Carlo method; Peptidomimetic compound; Conformational analysis; Molecular dynamics method; Theoretical study; Bromocarbon; NMR spectrometry; Experimental study; Fluorescence spectrometry; Reaction mechanism; Benzenic compound; Intramolecular hydrogen bond
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0284759

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.