Kathleen A. Turner

Porous, functional, poly(styrene-co-divinylbenzene) monoliths by RAFT polymerization

Herein we provide the first report of a new method for the preparation of porous functional poly(styrene-co-divinylbenzene) monoliths by use of reversible addition–fragmentation chain transfer (RAFT) polymerization. The method, exemplified by styrene–divinylbenzene copolymerization in the presence of 2-cyano-2-propyl dodecyl trithiocarbonate, provides control over polymerization kinetics, monolith morphology and surface functionality. Kinetic studies of monolith formation show a period of slow copolymerization, with a rate similar to RAFT homopolymerization of styrene, followed by rapid copolymerization, with a rate similar to that observed in conventional styrene–divinylbenzene copolymerization. The time to onset of rapid polymerization (gelation) and the monolith morphology depend strongly on the RAFT agent concentration. The RAFT-synthesized monoliths show a modified morphology with smaller pores and polymer globules when compared to non-RAFT monoliths, but importantly retain good flow properties. Retention of the thiocarbonylthio group within the monolith structure in an active form for surface-functionalization of the polymeric monoliths is demonstrated by the successful RAFT “grafting from” polymerization of (4-vinylphenyl)boronic acid. These functional monoliths have potential applications in chromatography and flow chemistry.

Binding inhibitors of the bacterial sliding clamp by design

The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β(2) sliding clamp is an essential component of the replicative machinery, providing a platform for recruitment and function of other replisomal components and ensuring polymerase processivity during DNA replication and repair. A single binding region of the clamp is utilized by its binding partners, which all contain conserved binding motifs. The C-terminal Leu and Phe residues of these motifs are integral to the binding interaction. We acquired three-dimensional structural information on the binding site in β(2) by a study of the binding of modified peptides. Development of a three-dimensional pharmacophore based on the C-terminal dipeptide of the motif enabled identification of compounds that on further development inhibited α-β(2) interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β(2), as a starting point for further inhibitor design.

Chapter Four – Structure and Function of Ecdysone Receptors—Interactions with Ecdysteroids and Synthetic Agonists

Abstract The binding of ecdysteroids and the bisacylhydrazine insecticide, tebufenozide, to recombinant ecdysone receptor ligand-binding domains from pest insects points to conserved and variable features of the receptors ligand-binding pocket. Fluorophores conjugated to the terminus of the ecdysteroid alkyl chain have surprisingly little effect on receptor binding, permitting the development of a fluorescence polarization chemical library screen that has led to the discovery of a new class of ecdysone receptor ligands, the methylene lactams. X-ray structures of ecdysone receptor ligand-binding domains have allowed identification of the conserved and variable features within the binding pocket. The structures offer explanations for the lepidopteran selectivity of the bisacylhydrazines, the effect of amino acid replacements on the binding of ecdysteroids and other chemistries, and the preference of a phytophagous pentatomomorphan for makisterone A; indeed, they speak to the control spectra of future ecdysone receptor-targeting insecticides. Possible ligands for nematode ecdysone receptor orthologs are also considered.

The chromium trioxide–3,5-dimethylpyrazole complex: a mild and selective reagent for the oxidation of cyclopropyl hydrocarbons

The title complex selectively oxidises the methylene unit adjacent to a cyclopropane ring producing synthetically useful yields of the corresponding cyclopropyl ketones and/or products resulting from cleavage of the three-membered ring.

Discovery of ectoparasiticidal hydrazonotrifluoromethanesulfonanilides.

A series of hydrazonotrifluorosulfonanilide derivatives were synthesized and evaluated for in vitro activity against the ectoparasites Ctenocephalides felis and Rhipicephalus sanguineus. Some compounds with excellent activity against tick were identified.

Asymmetric Synthesis of a Hydroxylated Nine-membered Lactone from Tartaric Acid using the Claisen Rearrangement

The synthesis of a hydroxylated vinyl-appended lactone, in five synthetic steps from tartaric acid, is reported. The C2-symmetrical bis-vinyl diol 12 was converted into the ketene acetal 14 via methylenation of the cyclic carbonate 13 or thermal elimination of benzeneselenenic acid from the selenoxide 17. In both cases, the in situ generated ketene acetal 14 underwent spontaneous Claisen rearrangement to give the nine-membered lactone (+)-15. Lactones of this type are potentially advanced precursors to simplified eleutherobin analogues or other medium-ring lactone natural products.

Construction of the 1,2,3,4-tetrahydro-1,4,6,2-oxathiazaphosphorine ring system

The novel 1,2,3,4-tetrahydro-1,4,6,2-oxathiazaphosphorine ring system has been prepared by reaction of the sodium salt of diethyl mercaptomethylphosphonate with nitrile oxides, followed by cyclization of the resulting hydroximinoyl sulfide. The stability of the new ring system is investigated.

Structural Reevaluation of the Crystalline Methylenedigallic Acids

Analysis of the products of the previously reported conditions for the preparation of crystalline methylenedigallic acids from gallic acid has revealed that the water-insoluble acid is a tetrahomodioxacalix[4]arene and the water-soluble acid is a trimeric species.