A Peptoid Square Helix via Synergistic Control of Backbone Dihedral Angles.

The continued expansion of the fields of macromolecular chemistry and nanoscience has motivated the development of new secondary structures that can serve as architectural elements of innovative materials, molecular machines, biological probes, and even commercial medicines. Synthetic foldamers are particularly attractive systems for developing such elements because they are specifically designed to facilitate synthetic manipulation and functional diversity. However, relatively few predictive design principles exist that permit both rational and modular control of foldamer secondary structure, while maintaining the capacity for facile diversification of displayed functionality. We demonstrate here that the synergistic application of two such principles in the design of peptoid foldamers yields a new and unique secondary structure that we term an "η-helix" due to its repeating turns, which are highly reminiscent of peptide ß-turns. Solution-phase structures of η-helices were obtained by simulated annealing using NOE-derived distance restraints, and the NMR spectra of a series of designed η-helices were altogether consistent with the primary adoption of this structure. The structure is resilient to solvent and temperature changes, and accommodates diversification without requiring postsynthetic manipulation. The unique shape, broad structural stability, and synthetic accessibility of η-helices could facilitate their utilization in a wide range of applications.

Tandem Incorporation of Enantiomeric Residues Engenders Discrete Peptoid Structures.

A new peptoid design strategy entailing the concurrent inclusion of enantiomeric side chains enabled the construction of several new structural motifs, including a newly characterized "ω-strand". This new architectural technique significantly expands peptoid structural and functional space and can potentially be applied to other foldameric systems.

"Bridged" n→π* interactions can stabilize peptoid helices.

Peptoids are an increasingly important class of peptidomimetic foldamers comprised of N-alkylglycine units that have been successfully developed as antimicrobial agents, lung surfactant replacements, enzyme inhibitors, and catalysts, among many other applications. Since peptoid secondary structures can be crucial to their desired functions, significant efforts have been devoted to developing means of modularly controlling peptoid backbone amide cis-trans isomerism using side chains. Strategic engineering of interactions between side chain aromatic rings and backbone cis-amides (n→π*(Ar) interactions) is an attractive strategy for stabilizing helical structures in N-a-chiral aromatic peptoids, which are among the most utilized classes of structured peptoids. Herein, we report the first detailed computational and experimental study of n→π*(Ar) interactions in models of peptoids containing backbone thioamides, which we term "thiopeptoids". Our work has revealed that these interactions significantly affect amide rotamerism in both peptoid and thiopeptoid models via a newly characterized "bridged" mode of interaction mediated by the N-α-C-H σ orbitals. Overall, this work elucidates new strategies for controlling both peptoid and thiopeptoid folding and suggests that thiopeptoids will be highly structured and therefore potentially useful as therapeutics, biological probes, and nanostructural engineering elements.

New strategies for the design of folded peptoids revealed by a survey of noncovalent interactions in model systems.

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-->pi*, 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-alpha-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-->pi* 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.

Regio- and stereoselective synthesis of fluoroalkenes by directed Au(I) catalysis.

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.

Tuning peptoid secondary structure with pentafluoroaromatic functionality: a new design paradigm for the construction of discretely folded peptoid structures.

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.

N-[1-(Pentafluorophenyl)ethyl]acetamide.

The title compound, C10H8F5NO, crystallizes as a racemate with four symmetry-independent molecules in the asymmetric unit. The four molecules form two hydrogen-bonded pairs. Each pair is a building unit of an independent C4 chain propagating parallel to the ab plane.

Interception of quorum sensing in Staphylococcus aureus: a new niche for peptidomimetics.

Pathogenesis in Staphylococcus aureus is dependent on local cell density and is regulated in part by small macrocyclic peptides. Natural and artificial peptide inhibitors of this quorum sensing response have been synthesized and evaluated in structure-activity relationship studies. These investigations have illuminated the quorum sensing mechanism and set the stage for the design of biostable, peptidomimetic inhibitors that could be developed ultimately as therapeutics.

Expedient synthesis and design strategies for new peptoid construction.

[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.