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The development of functional materials and smart surfaces has received tremendous attention in recent years. The anchoring of molecular machines and the transfer of their properties on to solid substrates may facilitate the design of new smart devices. Herein, we report an approach to the covalent modification of glassy carbon electrodes with electrochemically responsive tris(N-phenylureido)calix[6]arene-based pseudorotaxanes. The main focus of this study has been the electrochemically driven threading/de-threading process of the redox active dialkylviologen axial component of the supramolecular assemble. After the creation of an amine monolayer on the electrode, pseudorotaxane systems were generated at the surface using different approaches. It was revealed, through electrochemical investigations, that the reversibility of the threading/de-threading process of the axle depended on the nature of the alkyl substituents on the axle.

We describe the development of a small-molecule mimic of Xaa-trans-Pro dipeptide in poly-l-proline type II helix conformation, based upon a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane core structure. Stereoselective synthesis of the mimic from l-pyroglutamic acid is achieved in twelve linear steps and 9.9% yield. Configurational and conformational analyses are conducted using a combination of (1)H NMR spectroscopy, X-ray crystallography and circular dichroism spectroscopy; and evaluation of the mimic as a promising surrogate dipeptide, in a protein-protein interaction between the SH3 domain of human Fyn kinase (Fyn SH3) and peptidomimetics of its biological ligand, are conducted by (1)H-(15)N HSQC NMR titration experiments.

We report the combinatorial preparation and high-throughput screening of a library of modified electrodes designed to catalyze the oxidation of NADH. Sixty glassy carbon electrodes were covalently modified with ruthenium(II) or zinc(II) complexes bearing the redox active 1,10-phenanthroline-5,6-dione (phendione) ligand by electrochemical functionalization using one of four different linkers, followed by attachment of one of five different phendione metal complexes using combinatorial solid-phase synthesis methodology. This gave a library with three replicates of each of 20 different electrode modifications. This library was electrochemically screened in high-throughput (HTP) mode using cyclic voltammetry. The members of the library were evaluated with regard to the surface coverage, midpeak potential, and voltammetric peak separation for the phendione ligand, and their catalytic activity toward NADH oxidation. The surface coverage was found to depend on the length and flexibility of the linker and the geometry of the metal complex. The choices of linker and metal complex were also found to have significant impact on the kinetics of the reaction between the 1,10-phenanthroline-5,6-dione ligand and NADH. The rate constants for the reaction were obtained by analyzing the catalytic currents as a function of NADH concentration and scan rate, and the influence of the surface molecular architecture on the kinetics was evaluated.

Samarium(II) diiodide mediated intramolecular cyclisation of mixed enone–enoate substrates in THF/MeOH is described. Spirocyclic ethers are obtained, and the stereodefined preparation of 1-oxaspiro[4.4]nonan-7-one products is included.

The structures of N-benzyl-N'-{6-[(4-carboxylatobenzyl)aminocarbonyl]-2-pyridylmethyl}guanidinium, C(23)H(23)N(5)O(3), (I), and N-[2-(benzylaminocarbonyl)ethyl]-N'-{6-[(4-carboxylatobenzyl)aminocarbonyl]-2-pyridylmethyl}guanidinium monohydrate, C(26)H(28)N(6)O(4).H(2)O, (II), both form three-dimensional supramolecular hydrogen-bonded networks based on a dimeric primary synthon involving carboxylate-guanidinium linkages. The differences in the geometries and hydrogen-bonding connectivities are driven by the additional methylpropionamide group and water of crystallization of (II).

Glassy carbon electrodes functionalised with two redox centres have been prepared by using electrochemical and solid-phase synthetic methodologies. Initially the individual coupling of anthraquinone, nitrobenzene and dihydroxybenzene to a glassy carbon electrode bearing an ethylenediamine linker was optimised by using different coupling agents and conditions. Bifunctionalisation was then carried out, either simultaneously, with a mixture of nitrobenzene and dihydroxybenzene, or sequentially, with anthraquinone then nitrobenzene and with anthraquinone then dihydroxybenzene. Characterisation of these electrodes by cyclic voltammetry and differential pulse voltammetry clearly proved the attachment of the pairs of redox centres to the glassy carbon electrode. Their partial surface coverages can be controlled by varying the coupling agent or by controlling the substrate concentration during the solid-phase coupling process. Trifunctionalisation was also realised according to this methodology.

We report the preparation, using electrochemical and solid-phase synthesis, and characterisation of a 26 member library of 13 dihydroxybenzene derivatives covalently attached to glassy carbon through ethylenediamine (EDA) and C(6)H(4)CH(2)NH linkers. First, Boc-protected EDA or Boc-NHCH(2)C(6)H(4) were electrochemically attached to the GC surface. After Boc-deprotection, dimethoxybenzoyl chlorides were coupled to the EDA and C(6)H(4)CH(2)NH linkers using solid-phase synthesis followed by deprotection of the methoxy groups to give the corresponding dihydroxybenzene compounds. Surface coverage and electrochemical parameters of the dihydroxybenzene modified electrodes were evaluated in parallel using cyclic voltammetry. The mid-peak potentials, E(mp), and surface coverages for the 13 dihydroxybenzene derivatives were found to be independent of the choice of linker. The mid-peak potentials of the immobilised dihydroxybenzene derivatives varied between 0.0 and 260 mV vs. SCE and their surface coverages varied between 0.07 and 1.1 nmol cm(-2), depending on the pattern of substitution of the dihydroxybenzene ring. The electrocatalytic activities of the library were evaluated for mediation of NADH oxidation, and the ortho-dihydroxybenzene derivatives were found to have higher catalytic activity.

A series of readily prepared bifunctional catalysts promote the Michael addition of cyclohexanone to trans-?-nitrostyrene with excellent asymmetric induction. The enantioselection (up to 97%) and diastereoselection (up to 95:5) is comparable to other pyrrolidine­-thiourea organocatalysts recently reported, however, reaction times are often shorter

Samarium(II) diiodide-mediated intramolecular cyclodimerisation of simple bis-enones and -enoates in THF/MeOH has been investigated. Spirocyclic and elaborated polycyclic products, including stereodefined cis-bicyclo[3.3.0]octane and trans-bicyclo[4.3.0]nonanes, are obtained in synthetically useful yield.

Two dialkylated isocyanides were first synthesised from simple starting materials and then used as building blocks for the synthesis of indolizidines via a novel radical cyclisation/N-alkylation/ring closing metathesis strategy. Several functionalised indolizidines were accessed in good to excellent yields.

A new macrocyclic receptor incorporating a thiourea moiety has been synthesised. Crystal structures of the macrocycle showed that the receptor has a rigid backbone but the thiourea moiety can orientate itself to bind to a DMSO solvent molecule. Force-field (MMFFs) calculations were performed to model the macrocycle and its binding properties with respect to N-protected amino acids, which were measured experimentally by NMR titration. Binding free energies were calculated by using the mode integration algorithm (MINTA) or free-energy perturbation (FEP). Excellent qualitative agreement with experiment was obtained. To further exploit the accuracy of the free-energy predictions for this system, the faster free-energy algorithm MINTA was used as a prediction tool to test the binding affinity of the macrocycle towards a series of several other amino acid derivatives, which speeded up considerably the screening process and reduced laboratory costs.

Split-and-mix peptide libraries have been encoded by capping cleavable, laddered sequences with p-bromobenzoic acid, allowing rapid analysis of the cleaved ladder fragments by mass spectrometry. The encoding methodology has been applied to the synthesis of libraries of peptide receptors and a library of tripeptides functionalised with a bicyclic guanidinium unit has been successfully screened to identify binding partners for Val-Val-Ile-Ala, the C-terminal tetrapeptide sequence of the amyloid- protein, A(1-42).

Different extracts of Caesalpinia mimosoides Lamk. (Leguminosae) were tested against eight human pathogenic bacteria and six fungal strains by the disc diffusion method. Among these extracts, the aqueous and the ethanolic extracts showed potent activity against some tested microorganisms. Subsequently, the latter extract was fractionated by means of Sephadex LH-20 column chromatography. A bioactive substance, responsible for the antimicrobial property was separated, and its structure was assigned as a known compound, gallic acid, by extensive chromatographic and spectroscopic analyses.

Libraries of "unsymmetrical" tweezer receptors, featuring a guanidinium head group as a carboxylate binding site and two independently synthesized peptidic arms, have been prepared and screened to identify receptors for the N-Ac-Lys-D-Ala-D-Ala tripeptide sequence. The binding properties of one such receptor structure, with dye-labeled N-Ac-Lys-D-Ala-D-Ala, were investigated. These studies demonstrated that when attached to the solid-phase, the receptor binds dye-labeled N-Ac-Lys-D-Ala-D-Ala, in buffered aqueous media, with mM binding affinity.

A series of chiral bisthiourea macrocycles 1-4 have been prepared and their binding properties with various dicarboxylate salts have been examined by using NMR titration and isothermal calorimetry experiments. Macrocycle 1, in particular, favours the 1:1 binding of N-protected L-glutamate and aspartate, but favours 1:2 binding of the corresponding D-amino acids in polar solvents (dimethyl sulfoxide and acetonitrile). The macrocycles, however, do not bind carboxylates at all in the less competitive solvent chloroform. The binding properties of these macrocyles are sensitive to small structural changes as demonstrated by the altered binding properties of macrocycles 2-4 compared with 1.

Relative binding free energies of amino acid derivatives to the host macrobicycle 12 in chloroform are calculated to determine the effect of stereochemistry and amide bond conformation. Simulations are performed for three different amino acid derivatives using Monte Carlo simulations, free energy perturbations, and the generalized Born/surface area solvation model. The free energy results support previous experimental findings that the l enantiomers of N-acetyl phenylalanine carboxylate and N-acetyl alanine carboxylate bind preferentially over the d enantiomers and that the amide bond is in the cis conformation for the bound l enantiomers. The enantioselectivity arises because of better shape complementarity, and the cis stabilization is achieved by a selective hydrogen bond to the cavity rim of the host and a remote steric stabilization of the side-chain χ1 dihedral angle. This computational approach was also applied to N-acetyl glycine carboxylate and indicated that, for this amino acid derivative, both...

The trifluoroacetyl moiety has been used as a new protecting group for guanidine functionality. The protecting group is easily cleaved under mild basic conditions and is complementary to the Boc, Cbz, and Ddpe protecting groups. The protecting group can be applied to peptide synthesis in solution as well as on a solid phase as it is orthogonal to a Boc and Cbz strategy and semiorthogonal to an Fmoc strategy.

A library of “tweezer” receptors, incorporating a guanidinium “head group” and two peptide derived side arms has been prepared on the solid-phase using an orthogonally protected guanidinium scaffold 12. The library was screened with various tripeptide derivatives in an aqueous solvent system. A tweezer receptor 25 for the side chain protected tripeptide 19 was identified from the screening experiments. Receptor 25 was resynthesised and solution binding studies were carried out, which revealed that 25 binds to tripeptide 19 with Ka=8.2×104±2.5×104 (15 % DMSO/H2O, pH 8.75) and with appreciable selectivity over the tripeptide enantiomer 22 and the side chain deprotected tripeptide 20.

A library of diamidopyridine derived tweezer receptors with peptidic side-arms has been prepared. Screening experiments with the library and a dye-labelled tripeptide l -Glu– l -Ser– l -Val–OH showed excellent selectivity (strong binding of the dye-labelled guest to ∼0.2% of resin-bound library members was observed) and led to the identification of a tweezer receptor structure, which was shown to bind the tripeptide with good selectivity over related tripeptide sequences. Analogous screening experiments with the side-chain protected tripeptide l -Glu(OtBu)– l -Ser(tBu)– l -Val–OH, showed little selectivity for any particular library member. The results are discussed in relation to previous screening experiments, using the same tripeptide guests, with related tweezer receptor libraries, which differ by one methylene in the separation of the diamidopyridine unit from the peptidic side-arms of the tweezer receptors.

Split-and-mix libraries of resin-bound "tweezer" receptors have been prepared and screened to identify receptors for dye-labelled tripeptides. The receptors incorporate a diamidopyridine unit to serve as a specific recognition site for the CO2H group, leading to strong and selective receptors for peptide guests with a CO2H terminus. The role of the dye-label, attached to the peptide guest to allow visualisation of selective recognition events in the screening experiments, has also been examined and was found to have a significant influence on the binding selectivities.

The SmI2 mediated cascade cyclisations of several methylenecyclopropyl ketones have been examined and found to proceed with high diastereoselectivity, which is critically dependent on the presence of HMPA in the reaction. In one case the radical species at the end of the cascade sequence underwent an unexpected and highly stereoselective dimerisation. The cascade methodology has been applied to a short synthesis of (±)-paeonilactone B and of (±)-6-epi-paeonilactone A.

A series of acyclic thiourea derivatives, designed to create a cleft with four hydrogen bond donors suitable for carboxylate recognition, have been prepared, and their ability to bind to N-protected amino acid carboxylate salts has been investigated. The crystal structure of one of the thioureas has been determined showing that it forms a hydrogen bonded centrosymmetric dimer in the solid-state, in a conformation appropriate for the desired binding of carboxylates. The thioureas show good discrimination between different amino acids and those thioureas incorporating chiral moieties show moderate enantioselectivity for a range of amino acid derivatives.

Radical cascade cyclisation of methylenecyclopropyl cyclohexanone adducts, using samarium diiodide to generate an initial ketyl radical, provide a short route to tricyclic ethers, and the stereochemical outcome can be influenced by the solvent used for the reaction.

Addition of lithium bis(methylenecyclopropyl)cuprates to acetoxy azetidinones gives methylenecyclopropyl azetidinones, which can be converted to various radical cyclisation precursors. Attempted 4-exo cyclisation of 3 led only to reduced product, while cyclisation of 5, using CuCl/bipy, gave a carbacephem, via a 5-exo cyclisation, but in low yield. Cyclisation of 6 and 7, however, gave novel tricyclic β-lactams, as the result of 7-endo cyclisation, in good yield, and a cyclisation of bromide 23 led to the tricyclic β-lactam 24, via a radical cascade sequence.

Two new receptors, 9 and 13, have been prepared, utilising a pyridyl aryl ether unit in the rim of the macrobicyclic structure, and the crystal structures for both of these receptors are reported. The presence of the pyridyl unit provides additional hydrogen bonding functionality in comparison to earlier structures of this type, and 9 is an effective receptor for N-acetyl L-asparagine carboxylate in CH2Cl2.

A combinatorial library of "tweezer" receptors, which incorporate a diamidopyridine unit to provide a specific binding site for a CO2H group (see picture), can be screened to identify sequence-selective receptors for chosen peptide guests with a CO2H terminus.

Eine kombinatorische Bibliothek von pinzettenformigen Rezeptoren, in die eine Diamidopyridin-Einheit als spezifische Bindungsstelle fur eine CO2H-Gruppe eingebaut ist (siehe Bild), wurde durchmustert, um einen sequenzspezifischen Rezeptor fur ausgewahlte Peptidliganden mit einem CO2H-Terminus zu identifizieren.

A novel cascade sequence, that begins with the samarium(II) iodide mediated formation of a ketyl radical, leads to a primary alkyl radical, which appears to be partially ‘protected’ from the anticipated further reduction to an organosamarium, and instead undergoes a highly stereoselective dimerisation.

The Lewis acid mediated cyclisation of various methylenecyclopropyl ketones, ketals and aldehydes has been investigated as a new route to six- and seven-membered rings. Cyclisation of aldehyde 6, ketal 9 and ketone 11 with TiCl4 gave cyclohexene products, and cyclisation of ketal 10 gave a dichlorocycloheptene, all via nucleophilic addition of the methylenecyclopropyl π bond to the activated carbonyl. Cyclisation of ketone 12, however, with SnCl4, gave a cyclopentanol 21, presumably via nucleophilic addition of a cyclopropyl σ bond to the activated carbonyl.

Synthetic receptors for peptides and amino acid derivatives are of considerable interest because of their direct relevance to many biological peptide–protein complexes, and may also lead, for example, to new biosensors, therapeutics and catalysts for peptide hydrolysis. Macrocycle 1 is a selective receptor for various dipeptide derivatives in chloroform, and most notably shows a strong preference for N-Cbz-β-alanyl amino acids over N-Cbz-β-alanyl lactic acids.

A 1000-member, biased library of tripeptides, attached to TentaGel resin via the amino terminus, has been screened with dansyl-labeled tweezer receptor 4 in water. The tweezer receptor was found to bind to ∼3% of the library members and, following sequencing of 20 beads using a novel coding strategy, showed 95% selectivity for Val at the carboxy terminus of the tripeptides and 40% selectivity for Glu(OtBu) at the amino terminus. Although complicated by solubility issues, binding of one of the tripeptides selected from the screening experiments, Z-Glu(OtBu)-Ser(OtBu)-Val-OH, to tweezer 4 was measured by microcalorimetry to have an association constant, Kassoc = 4 × 105 ± 5 × 104 M-1 (in sodium borate buffer containing 16.7% DMSO, pH 9.2) and presumably results from a combination of a carboxylate−guanidinium interaction, β-sheetlike hydrogen bonding with the sidearms of the tweezer, and hydrophobic interactions.

1,2 Disubstituted methylenecyclopropyl bromides, 6 and 11, undergo radical cascade reactions, involving cyclisation, ring-opening and further cyclisation, to give cis bicyclic products in 67% and 41% yields respectively.

A synthetic route to a tetrathiafulvalene (TTF) derived aspartic acid derivative 18, with suitable orthogonal protecting groups has been developed. The aspartic acid derivative 18 can be used in the synthesis of peptides, as exemplified by the synthesis of di-, tri- and tetra-peptides 21–23. Preliminary electrochemical studies of these novel peptides indicate that they may well undergo conformational reorganisation upon oxidation of the TTF moieties.

The lithium enolate Z-11 derived from methyl 3-dimethyl(phenyl)silylbutanoate reacts with the N-silylimines of cinnamaldehyde 12, of 3-trimethylsilylpropynal 18, and of 3-trimethylsilylpropenal 19 to give β-lactams with a high level of stereoselection in favour of the cis isomers 13, 20 and 21, respectively. The dimethyl(phenyl)silyl group in the N-benzyldihydro derivative of the β-lactam 13 was converted into a hydroxy group by protodesilylation followed by peracid oxidation. The aldol product 24 of acetaldehyde with the same enolate Z-11 was converted into the corresponding O-benzyl hydroxamate 25, which gave the trans-β-lactam 26 by a Mitsunobu reaction. A similar aldol reaction using 3-dimethyl(phenyl)silylpropanal and the lithium Z-enolate derived from benzyl 3-dimethyl(phenyl)silylbutanoate gave the aldol 32, which was converted successively by way of the O-benzyl hydroxamate 33 and the trans-β-lactam 34 into the disilylated trans-β-lactam 35. Silyl-to-hydroxy conversion of both silyl groups and N,O-acetonide formation gave the known intermediate 36. Another Mitsunobu reaction with formic acid gave the C-8 epimer 2, which has previously been converted into (±)-thienamycin 1.

Macrocyclic receptor 9 , has been prepared in homochiral form. The receptor shows selectivity for certain dipeptides, and most notably a strong preference for N -Cbz-β-alanyl amino acids over N -Cbz-β-alanyl lactic acids.

4-[(3'-Carbohydroxypropyl)thio]-5-(methylthio)tetrathiafulvalene was synthesized and used as a mediator for the oxidation of glucose oxidase both free in solution and after covalent attachment to the enzyme through carbodiimide coupling to amine residues in the protein, The modified enzyme was characterized by isoelectric focusing gel electrophoresis and found to have a higher pi than the native enzyme, Electrochemical studies show that the singly oxidized tetrathiafulvalene derivative attached to the enzyme can act as a mediator for the direct reoxidation of the enzyme at electrode surfaces, whereas the doubly oxidized dication is not a mediator. Similar results are found for mediation by the tetrathiafulvalene derivative in solution, The application of the modified enzyme in membrane enzyme electrodes was investigated, and the response were analyzed to give kinetic information about the modified enzyme kinetics, Our studies show that the modified enzyme has good stability on storage in the absence of glucose but is less stable during continuous operation in a glucose sensor, This appears to arise from reactions between the tetrathiafulvanene groups attached to the modified enzyme and traces of hydrogen peroxide generated by the enzymatic reaction of glucose with oxygen present in the solution.

Lewis acid mediated endo-cyclisation of trimethylsilylmethylenecyclopropyl imines provides a stereoselective route to indolizidines via a novel cascade sequence.

An appropriately functionalised guanidine has been connected to a solid support, allowing peptide chains to be attached by conventional solid phase synthesis. This provides the basis for the solid-phase synthesis of libraries of ‘tweezer’ receptors for peptides with a carboxylate terminus.

Dianionic and neutral bis TTF dithiolate mercury and nickel complexes have been prepared. X-ray structural studies show the geometry around the mercury to be tetrahedral and CV and esr measurements indicate very little interaction between the two TTF based ligands. Conductivity measurements on the neutral mercury complexes gave [sgrave]RT = 10−5 Scm−1 whereas for the neutral nickel complexes values of 10−2 -10−1 Scm−1 are observed. The salts [TTF]x[Fe(tdas)2] × = 2, 3/2 (Idas = 1,2,5-thiadiazole-3,4-dithiol) have been prepared by electrocrystallisation and show conductivities of 10−2 Scm−1 and 10−5 Scm−1 respectively. The former salt displays thermally activated magnetic behaviour and the latter shows a Curie-type temperature dependance.

Macrobicycle 12 has been synthesized and its binding properties with a range of N-acetyl amino acid carboxylates (as tetrabutylammonium salts) have been studied. While the binding results showed little selectivity for the various substrates investigated, detailed NMR studies have revealed that d-amino acid substrates bind predominantly on the outside of the macrobicycle cavity by a strong carboxylate−thiourea interaction, whereas l-amino acid substrates bind predominantly on the inside of the cavity also establishing a strong carboxylate−thiourea interaction but with the acetyl amide in a cis configuration. Molecular modeling studies suggest that the energetic penalty associated with adopting a cis amide configuration in the host−guest complex is compensated by intermolecular hydrogen bonds between the cis amide and the rim of the macrobicycle.

Three novel polymer-supported isocyanides have been synthesised, from commercial Wang and HMBA-AM resins, and reacted under radical conditions with 2-mercaptoethanol and ethanethiol to give the corresponding pyrrolidine or pyroglutamic acid derivatives in good yields.

6-exo Cyclisations of methylenecyclopropyl ketones, mediated by samarium diiodide, have been investigated with a series of substrates. The efficiency of the cyclisations are highly dependent on the stereochemistry of the cyclisation precursor.

A novel macrobicycle featuring an amidopyridine unit as a carboxylic acid binding site, and amide functionality to provide further hydrogen bonding interactions with suitable guests has been prepared. The ability of this novel macrobicycle to bind peptide derivatives has been investigated.

The radical cyclisations of methylenecyclopropane derivatives 8, 11, 12, 14 and 16 have been studied, and provide a route to spirocyclic systems.

Bis- and tris-tetrathiafulvalene (TTF) derivatives have been prepared by coupling together TTF monoacids and diacids with diaminopropane spacers. These new materials were successfully deposited to give Langmuir–Blodgett (LB) films, but the films generally showed low conductivity, except for one non-amphiphilic sample that had been doped with iodine (σrt= 6 × 10–3 S cm–1). This demonstrates that non-amphiphilic TTF derivatives can be used to prepare conducting LB films without the addition of stabilising materials such as fatty acids.

Alkenyl and alkynyl isocyanides were synthesised and then reacted, using microwave flash-heating technology, with thiophenol, 2-mercaptoethanol and ethanethiol, in the presence of a radical initiator, to give highly functionalised pyrrolines and pyroglutamates. Direct comparison with results obtained using traditional heating techniques showed the advantage of using the microwave technology in terms of faster reactions and better yields.