Neil J. Wells

Solid-phase dendrimer synthesis

Dendrimers are highly ordered, hyperbranched polymers with potential for a whole range of chemical applications. Solution‐phase synthesis of dendrimers is often challenging, requiring long reaction times and nontrivial purification; solid‐phase methodology, on the other hand, enables reactions to be driven to completion by using a large excess of reagents with trivial purification. In this paper we show that polyamidoamine dendrimers may be synthesized conveniently and efficiently on a solid support, and that these molecules are of good homogeneity as characterized by 1H‐ and 13C‐nmr and electrospray mass spectrometry. These solid‐phase dendrimers were used as a bead loading amplification tool in the synthesis of a hexapeptide library (Xaa–Gly–Gly–Phe–Leu–Lys) to allow single bead analysis as well as allowing the efficient synthesis of two dendrimer conjugates (Leu–enkephalin–Lys and Chlorambucil). This demonstrated that peptides and small drug molecules can be grown directly onto the dendrimer or onto a linker attached to the dendrimer periphery, enhancing general dendrimer utility.

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.

A highly enantioselective receptor for N-protected glutamate and anomalous solvent-dependent binding properties

The development of enantioselective receptors continues to be a challenging endeavor for supramolecular chemists, and enantioselective recognition of biologically relevant molecules in competitive solvents is particularly demanding.[1] Although numerous receptors have been developed for dicarboxylic acids and dicarboxylates,[2] only a few enantioselective receptors for chiral dicarboxylic acids (in the neutral diprotonated form) have been described,[3] and very few examples of enantioselective receptors for chiral dicarboxylates have been reported.[4] We recently described an acyclic monothiourea receptor 1a, which bound a range of N-protected amino acid carboxylate salts with modest enantioselectivity.[5] Building on this work, we have now prepared macrocyclic receptor 2, which features two thiourea moieties flanked by carboxypyridines and separated by a chiral diamine. The receptor was designed to produce a chiral pocket for dicarboxylates by forming up to eight hydrogen-bonding interactions with the carboxylate oxygen atoms and intramolecular hydrogen bonding with the pyridine unit to help preorganize[6] the receptor (Scheme 1). Binding measurements, by NMR titration and isothermal

Towards predictable transmembrane transport: QSAR analysis of anion binding and transport

The transport of anions across biological membranes by small molecules is a growing research field due to the potential therapeutic benefits of these compounds. However, little is known about the exact mechanism by which these drug-like molecules work and which molecular features make a good transporter. An extended series of 1-hexyl-3-phenylthioureas were synthesized, fully characterized (NMR, mass spectrometry, IR and single crystal diffraction) and their anion binding and anion transport properties were assessed using 1H NMR titration techniques and a variety of vesicle-based experiments. Quantitative structure–activity relationship (QSAR) analysis revealed that the anion binding abilities of the mono-thioureas are dominated by the (hydrogen bond) acidity of the thiourea NH function. Furthermore, mathematical models show that the experimental transmembrane anion transport ability is mainly dependent on the lipophilicity of the transporter (partitioning into the membrane), but smaller contributions of molecular size (diffusion) and hydrogen bond acidity (anion binding) were also present. Finally, we provide the first step towards predictable anion transport by employing the QSAR equations to estimate the transmembrane transport ability of four new compounds.

Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding

Small molecule synthetic anion transporters may have potential application as therapeutic agents for the treatment of diseases including cystic fibrosis and cancer. Understanding the factors that can dictate the anion transport activity of such transporters is a crucial step towards their application in biological systems. In this study a series of acylthiourea anion transporters were synthesised and their anion binding and transport properties in POPC bilayers have been investigated. The transport activity of these receptors is dominated by their lipophilicity, which is in turn dependent on both substituent effects and the formation and strength of an intramolecular hydrogen bond as inferred from DFT calculations. This is in contrast to simpler thiourea systems, in which the lipophilicity depends predominantly on substituent effects alone.

On the twist-bend nematic phase formed directly from the isotropic phase

Abstract The intriguing twist-bend nematic (NTB) phase is formed, primarily, by liquid crystal dimers having odd spacers. Typically, the phase is preceded by a nematic (N) phase via a weak first-order transition. Our aim is to obtain dimers where the NTB phase is formed directly from the isotropic (I) phase via a strong first-order phase transition. The analogy between such behaviour and that of the smectic A (SmA)–N–I sequence suggests that this new dimer will require a short spacer. This expectation is consistent with the prediction of a molecular field theory, since the decrease in the spacer length results in an increase in the molecular curvature. A vector of odd dimers based on benzoyloxybenzylidene mesogenic groups with terminal ethoxy groups has been synthesised with spacers composed of odd numbers of methylene groups. Spacers having 5, 7, 9 and 11 methylene groups are found to possess the conventional phase sequence NTB–N–I; surprisingly, for the propane spacer, the NTB phase is formed directly from the I phase. The properties of these dimers have been studied with care to ensure that the identification of the NTB phase is reliable. Graphical Abstract

Reactions of ‘pincer’ pyridine dicarbene complexes of Fe(0) with silanes

Reactions of Fe(C-N-C)(N2)2, 1a, or Fe(C-NMe-C)(N2)2, 1b, C-N-C = 2,6-bis(arylimidazol-2-ylidene)pyridine, C-NMe-C = 2,6-bis(arylimidazol-2-ylidene)-3,5-dimethylpyridine, aryl = 2,6-iPr2C6H3, with silanes are described. Complex 1a with excess SiPhH3 and complex 1b with excess Si(tol)H3, Ph = phenyl, C6H5, tol = 2-methylphenyl, gave the complexes [Fe(C-N-C)(SiH2Ph)2(2-H-SiH2Ph)], 2a, and [Fe(C-NMe-C)(SiH2tol)2(2-H-SiH2tol)], 2b, respectively. Complex 1b with excess SiPhH3 gave [Fe(C-NMe-C)(SiH2Ph)2(H)2], 3, which was formulated as a dihydride based on the relaxation time T1(min) in the 1H-NMR spectra. Reaction of 1a with SiPh2H2 gave complex [Fe(C-N-C)(SiHPh2)2(2-H2)], 4, while reaction with Si(mes)H3 gave complex [Fe(C-N-C)(SiH2mes)2(N2)], 5, mes = mesityl, 2,4,6-trimethylphenyl. The comparison of the reactivity with other pincer complexes of iron and the mechanism leading to 2a-5 are discussed.

Investigating the influence of (Deoxy)fluorination on the lipophilicity of non-UV-active fluorinated alkanols and carbohydrates by a new log P determination method

Abstract Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome for non‐UV‐active compounds. A new variation of the shake‐flask log P determination method is presented, enabling the measurement of log P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the log P values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported.

Detection of nerve agent via perturbation of supramolecular gel formation

The formation of tren-based tris-urea supramolecular gels in organic solvents is perturbed by the presence of the nerve agent soman providing a new method of sensing the presence of organophosphorus warfare agents.

Highly effective yet simple transmembrane anion transporters based upon ortho-phenylenediamine bis-ureas

Simple, highly fluorinated receptors are shown to function as highly effective transmembrane anion antiporters with the most active transporters rivalling the transport efficacy of natural anion transporter prodigiosin for bicarbonate.