Katrina A. Jolliffe

Hierarchical Self-Assembly of a Chiral Metal–Organic Framework Displaying Pronounced Porosity†

[Extract] Significant recent attention has been devoted to the development of useful self-assembled hybrid materials.[1] This is particularly the case for metal–organic frameworks (MOFs), which display properties such as regularity, porosity, robustness, and high surface area that lead to potential applications in areas such as catalysis, gas separation, and storage.[2, 3] Our research groups and others have been developing new methods for the synthesis of both discrete and extended metal–organic materials, with particular interest in the controlled generation of increased structural complexity.[4] Herein we report a hierarchical self-assembly strategy which has been used to synthesize a new metal–organic framework. This strategy differs from the commonly employed molecular building block (MBB) and secondary building unit (SBU) approaches, where single metal ions or small inorganic clusters (polyhedra) are linked by bridging (often carboxylate) ligands in a one-pot reaction.[5] In these approaches, substantial pore volume is achieved principally through the enthalpically favorable formation of an open framework overcoming the entropic penalties associated with the entrapment of solvent guest molecules. Kinetic control over the formation of the framework is achieved largely through the trial-and-error optimization of synthetic conditions to prevent formation of unwanted kinetic intermediates.[6]

Trifluoroethanethiol: An Additive for Efficient One-Pot Peptide Ligation−Desulfurization Chemistry

Native chemical ligation followed by desulfurization is a powerful strategy for the assembly of proteins. Here we describe the development of a high-yielding, one-pot ligation-desulfurization protocol that uses trifluoroethanethiol (TFET) as a novel thiol additive. The synthetic utility of this TFET-enabled methodology is demonstrated by the efficient multi-step one-pot syntheses of two tick-derived proteins, chimadanin and madanin-1, without the need for any intermediary purification.

Synthetic Strategies for the Design of Peptide/Polymer Conjugates

We review the advantages and drawbacks of the various synthetic strategies for conjugating peptides to synthetic polymers obtained from reversible-deactivation radical polymerization (also known as living radical polymerization, controlled radical polymerization, or controlled/living radical polymerization). By using a selection of examples, we summarize the concept behind divergent and convergent syntheses, which lead to the production of linear and grafted peptide/polymer conjugates. In the second section of this review, we present an overview of a near–universal convergent approach for the production of peptide/polymer conjugates, by combining reversible addition–fragmentation chain transfer (RAFT) polymerization and copper(I)–catalyzed Huisgen 1,3-dipolar cycloaddition reactions between an azide and an alkyne (CuAAC).

Chemoenzymatic methods for the enantioselective preparation of sesquiterpenoid natural products from aromatic precursors

The enantiomerically pure cis-1,2-dihydrocatechols 2, which are generated by enzymatic dihydroxylation of the corresponding aromatic, engage in regio- and stereo-controlled Diels-Alder cycloaddition reactions to give a range of synthetically useful bicyclo[2.2.2]octenes. Certain examples of the latter type of compound have been used as starting materials in the synthesis of the sesquiterpenoids (−)-patchoulenone and (−)-hirsutene.

Tuning colourimetric indicator displacement assays for naked-eye sensing of pyrophosphate in aqueous media

A library of anion receptors comprising cyclic peptide scaffolds bearing two (ZnII-DPA) anion binding sites have been synthesised and their anion binding abilities evaluated using colourimetric indicator displacement assays with three different indicators. The resulting chemosensing ensembles provided excellent discrimination between polyphosphate ions, with several of the receptor : indicator combinations providing naked-eye sensing of pyrophosphate ions in aqueous solutions containing more than 100 fold excess of ATP.

Synthetic transporters for sulfate: a new method for the direct detection of lipid bilayer sulfate transport

The transmembrane transport of anions by small synthetic molecules is a growing field in supramolecular chemistry and has focussed mainly on the transmembrane transport of chloride. On the other hand, the transport of the highly hydrophilic sulfate anion across lipid bilayers is much less developed, even though the inability to transport sulfate across cellular membranes has been linked to a variety of genetic diseases. Tris-thioureas possess high sulfate affinities and have been shown to be excellent chloride and bicarbonate transporters. Herein we report the sulfate transport abilities of a series of tris-ureas and tris-thioureas based on a tris(2-aminoethyl)amine or cyclopeptide scaffold. We have developed a new technique based on 33S NMR that can be used to monitor sulfate transport, using 33S-labelled sulfate and paramagnetic agents such as Mn2+ and Fe3+ to discriminate between intra- and extravesicular sulfate. Reasonable sulfate transport abilities were found for the reported tris-ureas and tris-thioureas, providing a starting point for the development of more powerful synthetic sulfate transporters that can be used in the treatment of certain channelopathies or as a model for biological sulfate transporters.

Modular design for the controlled production of polymeric nanotubes from polymer / peptide conjugates

We have established a new strategy to produce functional organic nanotubes of controlled structure from cyclic peptide/polymer conjugates. The structure guiding cyclic peptide motif was coupled to the polymeric chains viacopper-catalyzed azide–alkyne click reaction, to yield very well-defined conjugates. The resulting conjugates were then self-assembled into nanotubes in solution. We were able to control to some extent the length of the nanotubes, by modifying the length of the polymer chain as well as by mixing conjugates of different molecular weights together. In a similar fashion we were able to prepare functional tubes from a range of polymers including poly(butyl acrylate), poly(dimethyl amino ethyl acrylate), poly(acrylic acid), poly(styrene) and poly(hydroxyl ethyl acrylate), as well as tubes with mixed functionality, by self-assembling a mixture of conjugates of differing polymer functionality. This modular approach is a powerful technique to generate a large number of nanotubes of varying size and functionality, in a controlled and rapid process. We believe this new approach will permit the design of a wide range of functional organic nanotubes of controlled structure, in a simple and efficient process.

Synthesis of Self-assembling Cyclic Peptide-polymer Conjugates using Click Chemistry

Self-assembling cyclic peptide-polymer conjugates were prepared by ‘clicking’ polymers (prepared by RAFT polymerization) to an azide functionalized d-alt-l cyclic octapeptide via the Huisgen 1,3-dipolar cycloaddition reaction. Due to the high graft density, the efficiency of the click chemistry conjugation reaction was found to be highly dependent on the size of the polymer. At relatively low molecular weights, as many as four polymer chains could be grafted to each 8 residue cyclic peptide ring. Evidence for the self assembly of the conjugates into peptide-polymer nanotubes was observed by TEM and IR.

Thermal Gating in Lipid Membranes Using Thermoresponsive Cyclic Peptide–Polymer Conjugates

The partition and self-assembly of a new generation of cyclic peptide-polymer conjugates into well-defined phospholipid trans-bilayer channels is presented. By varying the structural parameters of the cyclic peptide-polymer conjugates through the ligation of hydrophobic and hydrophilic polymers, both the structure of the artificial channels using large unilamellar vesicle assays and the structural parameters required for phospholipid bilayer partitioning are elucidated. In addition, temperature was used as an external stimulus for the modulation of transbilayer channel formation without requiring the redesign and synthesis of the cyclic peptide core. The thermoresponsive character of the cyclic peptide-polymer conjugates lays the foundation for on-demand control over phospholipid transmembrane transport, which could lead to viable alternatives to current transport systems that traditionally rely on endocytic pathways.

Thiosquaramides: pH switchable anion transporters†

The transport of anions across cellular membranes is an important biological function governed by specialised proteins. In recent years, many small molecules have emerged that mimick the anion transport behaviour of these proteins, but only a few of these synthetic molecules also display the gating/switching behaviour seen in biological systems. A small series of thiosquaramides was synthesised and their pH-dependent chloride binding and anion transport behaviour was investigated using 1H NMR titrations, single crystal X-ray diffraction and a variety of vesicle-based techniques. Spectrophotometric titrations and DFT calculations revealed that the thiosquaramides are significantly more acidic than their oxosquaramide analogues, with pKa values between 4.0 and 9.0. This led to the observation that at pH 7.2 the anion transport ability of the thiosquaramides is fully switched OFF due to deprotonation of the receptor, but is completely switched ON at lower pH.