Non-Covalent Interactions Enforce Conformation in Switchable and Water-Soluble Diketopiperazine-Pyridine Foldamers.

To reach their potential as mimics of the dynamic molecules present in biological systems, foldamers must be designed to display stimulus-responsive behavior. Here we report such a foldamer architecture based on alternating pyridine-diketopiperazine linkers. Epimerization is conveniently prevented through a copper-catalyzed coupling protocol. The compounds' native unswitched conformation is first discovered in the solid and solution state. The foldamers can be solubilized in DMSO and pH 9.5 buffer, retaining conformational control to a large degree. Lastly, dynamic switching is demonstrated through treatment with acid, leading to behaviour we describe as stimulus-responsive sidechain reconfiguration.

Atropselective synthesis of N-aryl pyridones via dynamic kinetic resolution enabled by non-covalent interactions.

The dynamic kinetic resolution of C-N atropisomeric pyridones was achieved via asymmetric phase-transfer catalysis, exploiting a rotational barrier-lowering hydrogen bond in the starting materials. X-ray and NMR experiments revealed the presence of a barrier-raising ground state CH⋯π interaction in the product, supported by DFT calculations. A co-crystal of the quinidine-derived phase-transfer catalyst and substrate reveals key substrate-catalyst non-covalent interactions.

Conformationally Programmable Chiral Foldamers with Compact and Extended Domains Controlled by Monomer Structure.

Foldamers are an important class of abiotic macromolecules, with potential therapeutic applications in the disruption of protein-protein interactions. The majority adopt a single conformational motif such as a helix. A class of foldamer is now introduced where the choice of heterocycle within each monomer, coupled with a strong conformation-determining dipole repulsion effect, allows both helical and extended conformations to be selected. Combining these monomers into hetero-oligomers enables highly controlled exploration of conformational space and projection of side-chains along multiple vectors. The foldamers were rapidly constructed via an iterative deprotection-cross-coupling sequence, and their solid- and solution-phase conformations were analysed by X-ray crystallography and NMR and CD spectroscopy. These molecules may find applications in protein surface recognition where the interface does not involve canonical peptide secondary structures.

Hybrid Diphenylalkyne-Dipeptide Oligomers Induce Multistrand ß-Sheet Formation.

Functionalized diphenylalkynes provide a template for the presentation of protein-like surfaces composed of multistrand ß-sheets. The conformational properties of three-, four-, and seven-stranded systems have been investigated in the solid- and solution-state. This class of molecule may be suitable for the mediation of therapeutically relevant protein-protein interactions.

A Modular Synthesis of Conformationally Preorganised Extended ß-Strand Peptidomimetics.

A promising strategy for mediating protein-protein interactions is the use of non-peptidic mimics of secondary structural protein elements, such as the α-helix. Recent work has expanded the scope of this approach by providing proof-of-principle scaffolds that are conformationally biased to mimic the projection of side-chains from one face of another common secondary structural element-the ß-strand. Herein, we present a synthetic route that has key advantages over previous work: monomers bearing an amino acid side-chain were pre-formed before rapid assembly to peptidomimetics through a modular, iterative strategy. The resultant oligomers of alternating pyridyl and six-membered cyclic ureas accurately reproduce a recognition domain of several amino acid residues of a ß-strand, demonstrated herein by mimicry of the i, i+2, i+4 and i+6 residues.

A Modular Synthesis of Conformationally Preorganised Extended ß-Strand Peptidomimetics.

Invited for the cover of this issue is the group of Andrew D. Hamilton and Sam Thompson at the University of Oxford (UK). The image depicts a new class of conformationally constrained ß-strand mimetics mediating the interaction between two subunits of a protein that controls transcription. Read the full text of the article at 10.1002/chem.201501366.

ß-Strand mimetic foldamers rigidified through dipolar repulsion.

Many therapeutically relevant protein-protein interactions contain hot-spot regions on secondary structural elements, which contribute disproportionately to binding enthalpy. Mimicry of such α-helical regions has met with considerable success, however the analogous approach for the ß-strand has received less attention. Presented herein is a foldamer for strand mimicry in which dipolar repulsion is a central determinant of conformation. Computation as well as solution- and solid-phase data are consistent with an ensemble weighted almost exclusively in favor of the desired conformation.

Phase-transfer-catalysed synthesis of pyrroloindolines and pyridoindolines by a hydrogen-bond-assisted isocyanide cyclization cascade.

A cascade reaction that generates pyrrolo- and pyridoindoline motifs from isocyanide precursors under phase-transfer conditions is described. This transformation proceeds at room temperature in the presence of a quaternary ammonium catalyst and base to generate functionalized products containing an all-carbon quaternary stereocentre. Quantum chemical calculations demonstrated that intramolecular general acid catalysis plays a key accelerating role through stabilization of developing charge in the transition state, and that the reaction is best described as a 5-endo dig cyclization, rather than an anionic 6π electrocyclization. Investigations employing chiral phase-transfer catalysts have given promising selectivities to date.

Enantioselective one-pot synthesis of dihydroquinolones via BINOL-derived Lewis acid catalysis.

A high-yielding and diastereoselective route to biologically significant 2-aryl- and 2-alkyl-3-amido dihydroquinolones has been developed in up to 90 : 10 e.r. by employing a novel Lewis acidic BINOL-derived copper(ii) catalyst.

Remote conformational control of a molecular switch via methylation and deprotonation.

Exacting control over conformation in response to an external stimulus is the central focus of molecular switching. Here we describe the synthesis of a series of diphenylacetylene-based molecular switches, and examine their response to covalent modification and deprotonation at remote phenolic positions. A complex interplay between multiple intramolecular hydrogen bond donors and acceptors determines the global conformation.

A Lewis acid-mediated conformational switch.

Molecules that change conformation in response to a stimulus have numerous uses, such as artificial chemoreceptors, novel drug delivery strategies and liquid crystal technology. Here we describe the design, synthesis and conformational behaviour of an isonicotinamide-substituted diphenylacetylene upon recognition of Lewis acids, including metalloporphyrins. Binding of these at a remote site - the pyridyl nitrogen - increases hydrogen-bond donor ability of the proximal amide NH, causing an increased preference for the alkyne rotamer in which this hydrogen bond is maintained.

Redox-dependent conformational switching of diphenylacetylenes.

Herein we describe the design and synthesis of a redox-dependent single-molecule switch. Appending a ferrocene unit to a diphenylacetylene scaffold gives a redox-sensitive handle, which undergoes reversible one-electron oxidation, as demonstrated by cyclic voltammetry analysis. (1)H-NMR spectroscopy of the partially oxidized switch and control compounds suggests that oxidation to the ferrocenium cation induces a change in hydrogen bonding interactions that results in a conformational switch.

Atropisomeric Foldamers.

This concept article explores the emerging role of atropisomerism in foldamer chemistry, a field focussed on oligomers that adopt well-defined conformations through non-covalent interactions. Atropisomerism introduces a novel dimension to foldamer design by restricting rotational freedom around single bonds to dictate molecular shape with precision. Despite the prevalence of atropisomeric bonds in organic synthesis, their application within foldamers remains underexplored. Here, we discuss key developments in both backbone and sidechain atropisomerism, and suggest future directions for atropisomeric foldamers in the context of a recent surge in atropselective synthetic methods. We propose that judicious use of atropisomerism may serve as a transformative tool in the construction of shape-defined macromolecules.

Continuous Flow Epoxidation of Alkenes Using a Homogeneous Manganese Catalyst with Peracetic Acid.

Epoxidation of alkenes is a valuable transformation in the synthesis of fine chemicals. Described herein are the design and development of a continuous flow process for carrying out the epoxidation of alkenes with a homogeneous manganese catalyst at metal loadings as low as 0.05 mol%. In this process, peracetic acid is generated in situ and telescoped directly into the epoxidation reaction, thus reducing the risks associated with its handling and storage, which often limit its use at scale. This flow process lessens the safety hazards associated with both the exothermicity of this epoxidation reaction and the use of the highly reactive peracetic acid. Controlling the speciation of manganese/2-picolinic acid mixtures by varying the ligand:manganese ratio was key to the success of the reaction. This continuous flow process offers an inexpensive, sustainable, and scalable route to epoxides.

Asymmetric electrocyclic reactions.

This critical review offers an overview of asymmetric electrocyclic processes, where diastereo- or enantioselectivity is a consequence of the influence of a chiral component (be it substrate or catalyst) on the electrocyclic bond-forming process (195 references).

Rationally designed helical peptidomimetics disrupt α-synuclein fibrillation.

Misfolding of the human protein α-synuclein results in toxic fibrils and the aggregation of Lewy bodies, which are a hallmark of Parkinson's disease in brain tissue. Here we disclose a supramolecular approach where peptidomimetics are rationally designed and pre-organised to recognize the surface of native helical α-Syn by forming complementary contacts with key patches of protein surface composed of charged and hydrophobic residues. Under lipid-catalyzed conditions the mimetics slow the rate of aggregation (thioflavin-T assay) and disrupt the misfolding pathway (electron microscopy of aggregates). This hypothesis is supported by comparison with a series of negative control compounds and with circular dichroism spectroscopy. Given the approach relies on selective recognition of both amino acid sequence and conformation (helical secondary structure) there is potential to develop these compounds as tools to unravel the currently intractable structure-function relationships of (i) missense mutation, and (ii) amyloid polymorphism with disease pathogenesis.

Chiral, sequence-definable foldamer-derived macrocycles.

Nature's oligomeric macromolecules have been a long-standing source of inspiration for chemists producing foldamers. Natural systems are frequently conformationally stabilised by macrocyclisation, yet this approach has been rarely adopted in the field of foldamer chemistry. Here we present a new class of chiral cyclic trimers and tetramers formed by macrocyclisation of open-chain foldamer precursors. Symmetrical products are obtained via a [2 + 2] self-assembly approach, while full sequence control is demonstrated through linear synthesis and cyclisation of an unsymmetrical trimer. Structural characterisation is achieved through a combined X-ray and DFT approach, which indicates the tetramers adopt a near-planar conformation, while the trimers adopt a shallow bowl-like shape. Finally, a proof-of-concept experiment is conducted to demonstrate the macrocycles' capacity for cation binding.

Acid-mediated topological control in a functionalized foldamer.

Induced conformational change provides a powerful mechanism to modulate the structure and function of molecules. Here we describe the synthesis of chiral, surface-functionalized oligomeric pyridine/imidazolidin-2-one foldamers, and interrogate their acid-mediated transition between linear and helical topologies.

Ion-mediated conformational switches.

Molecular switches are ubiquitous in Nature and provide the basis of many forms of transport and signalling. Single synthetic molecules that change conformation, and thus function, reversibly in a stimulus-dependent manner are of great interest not only to chemists but society in general; myriad applications exist in storage, display, sensing and medicine. Here we describe recent developments in the area of ion-mediated switching.