Trevor J. Rutherford

Observations on the activation of methyl thioglycosides by iodine and its interhalogen compounds

Abstract Treatment of ‘armed’ methyl thiogalactosides with iodine in the absence of an acceptor alcohol results in thioglycoside epimerisation, whereas there is no effect on the corresponding ‘disarmed’ methyl thioglycosides. In contrast, iodine–hexamethyldisilane (which generates iodotrimethylsilane in situ) brings about epimerisation of ‘disarmed’ thioglycosides, ultimately giving rise to the corresponding α-glycosyl iodides on extended exposure. Cross-over experiments show the former iodine-promoted epimerisation process to be intermolecular, whereas the latter iodine–hexamethyldisilane-promoted epimerisation is intramolecular. Treatment of the same methyl thiogalactosides with iodine monobromide gives rise to the thermodynamically favoured α-glycosyl bromides, whereas reaction with iodine monochloride initially gives the kinetic β-glycosyl chlorides, which slowly epimerise to the thermodynamic α-linked products. Differences in the outcome of thioglycoside activation by I–I, I–Br and I–Cl suggest there may be scope for influencing the stereochemical course of thioglycoside-based glycosylation reactions through careful choice of promoter.

Synthesis, analysis and rearrangement of novel unnatural glucosinolates.

As part of a structure activity study to examine the interaction of glucosinolates with leaf surfaces, a number of glucosinolates were synthesised bearing novel side chain functionalities. These included 7-carboxyheptyl, heptyl, and naphthyl side chains. For the carboxyheptyl glucosinolate, a novel intramolecular rearrangement reaction was observed during the final deprotection step, which generated an ester attached to the C-3 of glucose. Studies by 1H NMR spectroscopy showed that the hydrophobic side chain associated with one face of the glucose ring and it was proposed that this was the driving force for the rearrangement. Similar hydrophobic interactions were also observed between the heptyl and naphthyl side chains and the glucose.

A method for the quantification of resin loading using 19F gel phase NMR spectroscopy and a new method for benzyl ether linker cleavage in solid phase chemistry

A simple and efficient method for monitoring and quantifying the extent of loading onto polymer resin supports for solid-phase synthesis using 19F gel-phase NMR spectroscopy is described. This assay was utilised in the synthesis of an inositol monophosphatase inhibitor on Merrifield resin. A series of Merrifield resin derived benzylic ethers were prepared and were cleaved from the resin when treated with SnCl4 at room temperature to give the expected alcohol, phenol or olefin. This new cleavage method was used to remove the inositol monophosphatase inhibitor from the resin. A method for quantifying polymer support loading, using 19F gel phase NMR spectroscopy and a facile method for the cleavage of Merrifield resin derivatives is described in the context of a solid phase synthesis of phosphatase inhibitor 6.

Tyrosine nitration and peroxonitrite (peroxynitrite) isomerisation:15N CIDNP NMR studies

In the presence of tyrosine, peroxonitrous acid forms nitrite, nitrate and 3-nitrotyrosine by radical processes.

Design, synthesis, structure and properties of an α-helix cap template derived from N-[(2S)-2-chloropropionyl]-(2S)-Pro-(2R)-Ala-(2S,4S)-4-thioPro-OMe which initiates α-helical structures

Abstract A strategy based upon removing the requirement for all of the carbonyl dipoles to align at the same time in the transition state leading to the cyclisation of N-[(2S)-2-chloropropionyl]-(2S)-Pro-(2R)-Ala-(2S,4S)-4-thioPro-OMe to a Zimm-Bragg type α-helix peptide intitator template was successful. Each amide bond of the 12-membered macrocyclic template existed in the trans-rotomeric form. Derivatives of the template were prepared by extending the C-terminus and these were characterised by NMR spectroscopy and restrained simulated annealing. In deuterochloroform solution at low temperature, separate sets of NMR signals were observed for two rapidly interconverting helical conformational isomers of the thioether macrocycle which possessed an appended trialkylammonium ion. A similar time-averaged conformation was also observed in aqueous solution. At −80 °C in d 2 -dichloromethane the rate of conformational exchange was slowed sufficiently to obtain resonance assignments and NOE data separately for each isomer. In the minor isomer (40%), the four carbonyl oxygen hydrogen-bond acceptors of the template are aligned in an α-helical conformation and in the major conformer the Pro 2 carbonyl dipole was anti-aligned with the other three dipoles. Thus, the conformers differ in the orientation of one carbonyl group. Molecular modelling calculations showed that the minor isomer was stabilised by coulombic interactions between the trialkylammonium salt and the carbonyl group dipole moments.

Comparison of solution-phase and solid-phase syntheses of a restrained proline-containing analogue of the nodularin macrocycle

Abstract The solution-phase synthesis of a restrained (2 S )-proline-containing analogue of the nodularin macrocycle, cyclo -[ β -Ala-(2 R )-Glu(α-OMe)-γ-(2 R )-Asp(α-OMe)-β-(2 S )-Phe-], is described and compared to two solid-phase syntheses of the same cyclic isopentapeptide diester; one in which Fmoc-(2 S )-Phe-β-Ala-(2 R )-Glu(α-OMe)-γ-(2 S )-Pro-(2 R )-Asp(α-O-Wang Resin)-β-OAllyl is deprotected and then cyclised on the resin and one in which this same precursor is removed from the resin prior to cyclisation.

Adaptation of an NMR signal suppression pulse sequence for the selective removal of benzylic methylene signals of benzyl ether-protected carbohydrates

Abstract Application of the DPFGSE-TOCSY pulse sequence permits the selective removal of benzylic signals from the 1 H NMR spectra of benzyl ether-protected glycosides. Anomeric proton signals, which have a similar chemical shift, can be readily re-introduced with the aid of a TOCSY sequence. This approach is useful in cases where intense spectral overlap does not permit the straightforward identification of anomeric signals, and hence definition of anomeric configuration or determination of anomeric ratios. The representative application of this pulse sequence to analysis of iodine-promoted thioglycoside activation is reported.

Synthesis and properties of mechanism-based inhibitors and probes for inositol monophosphatase derived from 6-O-(2′-hydroxyethyl)-(1R,2R,4R,6R)-cyclohexane-1,2,4,6-tetraol

The 1-phosphate, 2′-phosphate and 1, 2′-cyclic phosphate of 6-O-(2-hydroxyethyl)-cyclohexane-1,2,4,6-tetraol are synthesised and found to be good inhibitors of inositol monophosphatase; the stereochemistry of the most potent inhibitor, the (1R,2R,4R,6R)-1-phosphate, provides useful mechanistic insight into the action of this enzyme, the putative target for lithium therapy.

Synthesis and properties of a biocompatible analogue for β-turn protein structural motifs based on 5-amino-3-pentynoic acid

Abstract 5-Amino-3-pentynoic acid, a new ‘lightly’ constrained amino acid surrogate for glycylglycine and model for dipeptide homologues was prepared from propagylamine and methods were devised for its incorporation into linear oligopeptides through both C- and N-terminal extension.

The structure of the ionophoric antibiotic Na-tetronasin (M139603) in solution

The structure of the ionophoric antibiotic sodium tetronasin (M139603) in chloroform solution has been determined using NMR spectroscopic methods and is shown to contain a water molecule bound to the sodium which is hydrogen bonded to oxygens in the molecule.