Controlling the equilibria between backbone cis- and trans-amides in peptoids, or N-substituted glycine oligomers, constitutes a significant challenge in the construction of discretely folded peptoid structures. Through the analysis of a set of monomeric peptoid model systems, we have developed new and general strategies for controlling peptoid conformation that utilize local noncovalent interactions to regulate backbone amide rotameric equilibria, including n→π*, steric, and hydrogen bonding interactions. The chemical functionalities required to implement these strategies are typically confined to the peptoid side chains, preserve chirality at the side chain N-α-carbon known to engender peptoid structure, and are fully compatible with standard peptoid synthesis techniques. Our examinations of peptoid model systems have also elucidated how solvents affect various side chain-backbone interactions, revealing fundamental aspects of these noncovalent interactions in peptoids that were largely uncharacterized previously. As validation of our monomeric model systems, we extended the scope of this study to include peptoid oligomers and have now demonstrated the importance of local steric and n→π* interactions in dictating the structures of larger, folded peptoids. This new, modular design strategy has guided the construction of peptoids containing 1-naphthylethyl side chains, which we show can be utilized to effectively eliminate trans-amide rotamers from the peptoid backbone, yielding the most conformationally homogeneous class of peptoid structures yet reported in terms of amide rotamerism. Overall, this research has afforded a valuable and expansive set of design tools for the construction of both discretely folded peptoids and structurally-biased peptoid libraries, and should shape our understanding of peptoid folding.

We report that n→π* interactions are operative in peptoids and play a major role in controlling amide isomerism. These interactions can be tuned using α-chiral amide side chains known to promote peptoid folding. To our knowledge, this is the first report of n→π* interactions between amides in non-prolyl systems. Furthermore, we have characterized an n→π* interaction between backbone carbonyls and side chain aromatic rings that can dramatically stabilize the cis-amides required for peptoid helix formation. The tunability of both types of n→π* interactions in peptoids has significant implications for peptoid folding and could be exploited for the design of new peptoid architectures.

Peptoids, or oligomers of N-substituted glycine, are an important class of non-native polymers whose close structural similarity to natural alpha-peptides and ease of synthesis offer significant advantages for the study of biomolecular interactions and the development of biomimetics. Peptoids that are N-substituted with alpha-chiral aromatic side chains have been shown to adopt either helical or "threaded loop" conformations, depending upon solvent and oligomer length. Elucidation of the factors that impact peptoid conformation is essential for the development of general rules for the design of peptoids with discrete and novel structures. Here, we report the first study of the effects of pentafluoroaromatic functionality on the conformational profiles of peptoids. This work was enabled by the synthesis of a new, alpha-chiral amine building block, (S)-1-(pentafluorophenyl)ethylamine (S-2), which was found to be highly compatible with peptoid synthesis (delivering (S)-N-(1-(pentafluorophenyl)ethyl)glycine oligomers). The incorporation of this fluorinated monomer unit allowed us to probe both the potential for pi-stacking interactions along the faces of peptoid helices and the role of side chain electrostatics in peptoid folding. A series of homo- and heteropeptoids derived from S-2 and non-fluorinated, alpha-chiral aromatic amide side chains were synthesized and characterized by circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. Enhancement of pi-stacking by quadrupolar interactions did not appear to play a significant role in stabilizing the conformations of heteropeptoids with alternating fluorinated and non-fluorinated side chains. However, incorporation of (S)-N-(1-(pentafluorophenyl)ethyl)glycine monomers enforced helicity in peptoids that typically exhibit threaded loop conformations. Moreover, we found that the incorporation of a single (S)-N-(1-(pentafluorophenyl)ethyl)glycine monomer could be used to selectively promote looped or helical structure in this important peptoid class by tuning the electronics of nearby heteroatoms. The strategic installation of this monomer unit represents a new approach for the manipulation of canonical peptoid structure and the construction of novel peptoid architectures.

Au-catalyzed hydrofluorination reactions of a range of functionalized alkynes are reported. In the presence of an appropriate directing group, localized with particular spacing from the pendant alkyne, regioselective and predictable conversion of the alkyne to the Z-vinyl fluoride may be achieved. In selected cases, yields and selectivities are excellent. Additional experiments with two directing groups installed have established some initial principles with respect to a hierarchy of directing groups and their capacity for influencing hydrofluorination regioselectivity.Fluorine is an element of special interest in organic chemistry. Its electronegativity, highest of all the known elements, contributes to its special properties, which include formation of strong bonds to carbon, 1 low atomic polarizability, 2 and strong inductive characteristics. 3 The field of medicinal chemistry has especially benefited from the development of chemical techniques for incorporating fluorine into organic molecules. Fluorine is now routinely introduced to impart metabolic stability to medicinal compounds. 4 Coupled with its electronegativity, fluorine's small size has made it an attractive choice for isosteric substitutions of hydrogen or In light of the importance of fluoroalkenes, many efforts towards efficient regio-and stereoselective syntheses of these moieties have been reported. 7 Of these, we were especially intrigued by a methodology developed by Sadighi and coworkers employing a Au(I) catalyst 8 to add HF across an alkyne. 9 Using Et 3 N•3HF as a nucleophilic fluorine source, KHSO 4 as an additive, and various co-catalysts, trans-hydrofluorination was achieved in good yields (Scheme 1). Modest regioselectivity for alkyl/aryl alkyne substrates was improved by adding electron-withdrawing groups to the aromatic ring substituents. Although other alkyne hydrohalogenations using Au-catalysis have been reported, these reactions utilize electrophilically activated halogens, for the most part excluding fluorine. 10 Also, the substrate scope of these reactions has been limited to propargyl acetates.Given our interest in fluoroolefins as mechanistic probes, 6 we sought to expand the methodology for Au-catalyzed nucleophilic fluorination of alkynes by developing new avenues for regiocontrol that would expand both the utility and substrate scope of the reaction. Specifically, we envisioned a classical heteroatom-directed reaction that might confer a high degree of selectivity for a broad range of substrates. 11 Here we report the realization of this design in the carbonyl-directed hydrofluorination of alkynes under Au(I) catalysis. We demonstrate that this concept is broadly applicable and engenders regioselectivies that exceed those originally reported for this reaction system. As such, this methodology could facilitate access to new compounds for fundamental research and the development of pharmaceuticals.We commenced our investigations by examining ester 1. We were intrigued to observe that hydrofluorination of this subst...

[reaction: see text] A range of peptoids can be prepared efficiently using microwave-assisted solid-phase chemistry in a commercial reactor. This method is most effective for the installation of electronically deactivated benzylic amines. The systematic incorporation of these amines into peptoids can deliver oligomers capable of displaying unique and stable structural motifs-microwave-assisted solid-phase synthesis will enable their future study and application.