Exploring the applications of fluorine for peptoid structure induction

Abstract

Throughout this thesis we have sought to demonstrate the broad applicability of fluorine and fluorinated groups as tools to promote enhanced conformational preferences in α-peptoids. To this purpose, a range of new fluorinated peptoid monomers have been designed and synthetized, including non-bulky fluoro-alkyl, fluoroheteroaromatic, α-trifluoromethyl, perfluoro-(hetero)aryl and pentafluoro-sulfanylphenyl (NSF5Ph) based monomers. The effects that fluorine can impart on peptoid cis/trans amide bond preferences have been studied in simple model systems using both NMR and X-ray analysis. Through these studies fluorine has been found to exert a considerable effect over peptoid bond conformational preferences either as a result of direct amide Cα-carbon polarization as in the non-chiral aliphatic systems studied (Chapter 2), or by a combination of enhanced steric and inductive factors as in the case of α-trifluoromethyl peptoid residues examined (Chapter 3). In addition, a novel strategy based on the use of SNAr reactions for the synthesis of novel N-perfluoro and N-perfluoroheteroaryl model peptoid systems is described. Unlike N-alkyl type peptoids, N-aryl monomers have been shown to have a strongly defined preference for trans-amide configurations. As part of our work in this area we report the first ever example of a completely stable cis-amide N-aryl peptoid building block (Chapter 4). The NMR, X-ray and IR studies carried out to investigate the cause of such an exceptional conformational preference provided strong evidence that it arises due to a side-chain induced amide nitrogen sp3 pyramidalization and amide N-CO bond twisting. Finally, we have explored the synthesis, and properties of novel NSF5Ph peptoid monomers (Chapter 5). Structural analysis of different SF5Ph containing model systems revealed how the steric properties and the repulsive effects between SF5- groups promote significant deviations in the geometry of the inter-residue π-stacking interactions, which are critical for peptoid folding. The fine tuning of these long-range interactions may open the door for the design of new foldameric peptoid structures. The comparative CD analysis of non-fluorinated NPh based peptoids and the first oligomers ever synthetized carrying NSF5Ph residues gave further support to this hypothesis, and demonstrated that SF5- groups can indeed influence peptoid folding in extended sequences.