Beta-Aminoxy peptides as foldamers : synthesis and conformational studies

by Zhang, Yuhui

(Uncorrected OCR) Abstract of thesis entitled P-AMINOXY PEPTIDES AS NEW FOLDAMERS: SYNTHESIS AND CONFORMATIONAL STUDIES submitted by Zhang Yu-Hui for the degree of Doctor of Philosophy at The University of Hong Kong in August 2004 Due to the interest in structural modifications of a-amino acids, there have been numerous explorations of unnatural oligomers with well-defined secondary structures (foldamers). Replacing the y-carbon atoms in y-peptides with oxygen atoms leads to a new class of foldamers, 6-aminoxy peptides. In this project, a new series of oligomers based on p-aminoxy acids has been designed and synthesized. Conformational studies on these oligomers have helped to elucidate the nature of the folding of p-aminoxy peptides. Oligomers 1-4 of B22-aminoxy acids were synthesized. Conformational studies revealed that diamides 1 and 2 adopt a novel B N-O turn structure, featuring a nine-membered-ring intramolecular hydrogen bond between adjacent residues and another six-membered-ring intramolecular hydrogen bond between NH^+2 and NO;+|. A well-defined helical structure characterized by two consecutive P N-O turns is formed in triamides 3 and 4. The twisting of the amide carbonyl group at position i+2 +65.9?from the group at /' position in the X-ray structure of 4 suggests a novel l.lg helix. Several methods were developed to synthesize oligomers 13-18 of 6 -aminoxy acids with different side chains. The conformational properties of 13-18 were investigated using NMR, IR, CD spectroscopy, and X-ray crystallography. The B N-0 turns and P N-0 helices found in oligomers of p2'2-aminoxy acids are also present in those p3-aminoxy peptides 13-18. X-Ray crystal structures and NMR spectral analysis revealed that the N-0 bond in the p N-0 turns and p N-O helices induced by p3-aminoxy acids can be either anti or gauche to the Ca-Cp bond, depending on the size of the side chain. Both diamide 13 and triamide 18 display parallel sheet structures in the solid state and predominantly p N-0 turn and P N-0 helix conformations in non-polar solvents. Theoretical studies on a series of model diamides are consistent with the experimentally observed conformational features of these p3-aminoxy peptides. p23-Aminoxy peptides 52-58 of different stereochemical patterns were synthesized to study the effect of stereochemistry on the folding of P-aminoxy peptides. Conformational studies on 52-58 indicated that p2'3-aminoxy peptides 52-54 of anti configuration favor P N-0 turns and p N-0 helices in which the N-0 bond is gauche to the C?C|i bond; but for peptides 55-58 of syn configuration, an extended strand instead of p N-0 turns is adopted in the solid state of 55, and an equilibration between non-hydrogen-bonded state and hydrogen-bonded state was found in solutions of 55-58. rr V? >c"J^ fri^ XfV PNP ) \^~~~- ^ ll o PP^ O /X H U 1 xo 3 n2,2 p -aminoxy peptides >\ .oO ^N^ >v?V^ PP 1 H o 1 H o x X H 2 4 o N-?Pr H R O 13 R = CH3 14 R = CH3CH2 17 O O ?u ^ N' h A o o o 15 o x> X)' o 18 -O o 16 p -aminoxy peptides P^?rNX) 0 P H ^Y^N'?^YNY^P p2'J-aminoxy 1 H = o PP peptides 52 0 ^S H i O >an'?Ptn^aya 1 H ? o ^^J 53 55 Y^CX pKVP^ 54 pv?Yo 56 57 58