Thesis (Ph. D.)--University of Hong Kong, 1991.

Baylis-Hillman reactions using various aromatic aldehydes, activated alkenes and catalysts have been used to: - access an extensive range of poly-heterocyclic products;explore chemoselectivity; and optimise reaction efficiency. Chromone-3-carbaldehydes and chromone-2-carbaldehydes, prepared via Vielsmeier-Haack and Kostanecki-Robinson methodology, respectively, have been used as Baylis-Hillman substrates with four different catalysts, viz., 1,4-diazabicyclo[2.2.2]octane (DABCO), 3-hydroxyquinuclidine (3-HQ), imidazole and N’,N’,N’,N’- tetramethylpropanediamine (TMPDA), and with methyl vinyl ketone (MVK), methyl acrylate, cyclic enones (2-cyclohexen-1-one, 2-cyclopenten-1-one and chromones) as activated alkenes. Reactions of the chromone- -carbaldehydes with MVK afforded dimeric Baylis-Hillman adducts when catalyzed by DABCO but when the same reactions were repeated using 3-HQ as catalyst, the dimeric products were accompanied by tricyclic Baylis-Hillman adducts. Use of excess MVK, however, led to mixtures of the normal Baylis-Hillman adducts and the tricyclic adducts – interestingly, with the apparent absence of the dimeric products. While reactions of chromone-3-carbaldehydes with methyl acrylate afforded the normal Baylis-Hillman adducts, the chromone-2- carbaldehydes produced, instead, rearrangement products, consistent with an earlier, single observation. Reactions of 2-nitrobenzaldehydes with cyclic enones using imidazole as catalyst afforded the normal Baylis-Hillman adducts, reductive cyclisation of the 2-cyclohexen-1- one and 2-cyclopenten-1-one adducts, using acetic acid and iron powder, afforded the corresponding quinoline erivatives. Treatment of cyclic enones with pyridine-2-carbaldehydes and quinoline-2-carbaldehydes using TMPDA as catalyst generally gave the expected Baylis-Hillman adducts. However, indolizine derivatives were isolated directly from Baylis-Hillman reactions involving pyridine-2-carbaldehydes and 2-cyclohexen-1-one. The remaining Baylis-Hillman adducts were cyclized to the corresponding indolizines by treatment with acetic anhydride both under reflux and under microwave-assisted conditions, the latter approach providing remarkably rapid and efficient access to the polycyclic products. Computer modelling studies have been conducted on selected polycyclic products at the Molecular Mechanics (MM), Quantum Mechanical (QM) and Density Functional (DFT) levels. The theoretical results have been used to calculate UV, IR and NMR absorption data, which have been compared, in turn, with the experimental spectroscopic data. Use has also been made of the estreNova NMR prediction programme and, generally, good agreement has been observed between the predicted and experimental spectroscopic data.

The reaction of salicylaldehyde with various activated alkenes, viz., methyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl sulfone, phenyl vinylsulfonate, acrolein and acrylonitrile, under Baylis-Hillman conditions, has been found to proceed with the chemoselective formation of chromene derivatives. The reaction conditions have been optimised and chromene derivatives have been obtained in isolated yields up to 87 %. The generality of the reaction, using 1,4-diazabicyclo[2.2.2]octane (DABCO), as the catalyst, and a heterogeneous (chloroform-water) solvent system, has been established using a range of salicylaldehyde derivatives,. including 2-hydroxynaphthaldehyde. The formation of chromene derivatives, under these conditions, has been assumed to proceed via an initial, Baylis-Hillman reaction, followed by cyclisation involving intramolecular conjugate addition, and subsequent dehydration. Evidence supporting this sequence has been obtained from the isolation ofBaylis-Hillman products from reactions involving the use of tertbutylclimethylsilyl-protected salicylaldehyde, 4-hydroxybenzaldehyde and tert-butyl acrylate as substrates. The potential of the ''Baylis-Hillman zwitterion" to participate as a donor species in Michael-type addition reactions has been explored and a series of climeric products has been isolated. The Baylis-Hillman methodology has also been successfully extended to the synthesis of sulfurcontaining heterocyclic systems, and a range of 3-substituted thiochromenes has been obtained in moderate yields, using 2,2'-dithiobenzaldehyde and various activated alkenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. The electron-impact mass spectra of selected chromene and thiocbromene derivatives have been investigated permitting comparison of the fragmentation of the oxygen- and sulfur-containing analogues. In a study directed at the synthesis of potential HIV -1 protease inhibitors, chromene- and thiocbromene-containing analogues of the clinically useful drug, ritonavir, have been prepared. Thiochromene and chromene derivatives were converted to the corresponding 3 -carboxylic acids and coupled with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing cbromene and thiochromene termini in ca. 60% yield.

No description available.

A novel class of potential positron emission tomography (PET) radiotracers for imaging aminopeptidase N (also known as APN or CD13) and cannabinoid type 1 (CB1) receptors were designed and synthesised with an efficient chemical strategy. Both targets have remarkable diagnostic and therapeutic potential, in fact the CD13 receptors are over-expressed during tumour angiogenesis and the CB1 receptors are highly expressed in the brain playing important functions in several pathophysiological processes. The target compounds were obtained by means of oxime-bio-conjugation between fluoro-deoxy-carbohydrates, used as prosthetic groups, and hydroxylamine-functionalised cyclic NGR (asparagine-glycine-arginine) motif sequences for CD13 receptor and rimonabant-type pyrazoles for the CB1 receptor. In particular, aminooxy-cyclic NGR peptides were conjugated with the novel prosthetic group 5-FDR (5-fluoro-5-deoxy-D-ribose) and the aminooxy- pyrazole-type cannabinoid molecules were conjugated with both 5-FDR and with FDG (2-fluoro-2-deoxy-D-glucose). 5-FDR proved to be superior to FDG, as the bioconjugation reaction occurred in milder conditions (room temperature vs 100 °C) and at faster rate. Furthermore, we observed that the rate of the oxime bond formation depends on the solubility of the aminooxy-functionalized core used. In fact, the bioconjugation with hydrophilic cyclic aminooxy-NGR peptides was faster than in the case of lipophilic aminooxy-pyrazoles (10 min vs 20-30 min). The receptor affinity is decreased in the case of the CB1 receptors after conjugation with the fluoro-carbohydrates. This is not observed with the conjugated NGR peptides, which maintain similar affinity for the CD13 receptor compared with the unconjugated NGR. In conclusion, we have developed an efficient strategy for the synthesis of a novel class of CD13 ligands, which may be also produced in radiofluorinated form, and explored a novel bioconjugation strategy for CB1 receptor ligands. Both may have important applications in the development of PET tracers.

Ricin is a potent cyctotoxin with no known antidote. Chapter 1 provides background and context for this thesis, which is primarily focused on probing the active site of Ricin toxin A (RTA). Relevant information about Ricin, its use, method of action, and noteworthy contributions towards the discovery of Ricin A chain inhibitors are provided. Furthermore, a brief description of the assays used by our collaborators to monitor RTA inhibition is provided. Additionally, a great deal of this thesis pertains to a particular heterocycle, pterin, and thus the remainder of Chapter 1 is dedicated to pterins, their physical properties, biological relevance, and selected reports of pterin chemistry. Chapter 2 details preliminary research focused on the use of nucleic acid-based platforms as RTA inhibitors. Two specific nucleic acids were chosen, adenine and guanine, and the chapter is split to address them individually. Rational for their use is provided, as well as the synthetic strategies investigated. Both platforms showed significant interference with the analysis assay, most pronounced for the adenine series. A primary goal throughout this thesis is the identification of a simple, rapid method to provide a library of new compounds. To this end, discussion of improved synthetic routes are provided within the section dedicated to guanines. Initial investigation into pterins as a platform for RTA inhibitors is provided in Chapter 3. Much of this chapter is concerned with hurtles encountered while dealing with the poor solubility of pterins, purification, and limits in reaction scope. Finally this chapter details a significant discovery in pterin's utility, both in terms of synthetic ease and preference towards one regioisomer over another. A variety of amides are initially used to probe the active site for significant interactions to the pterin pendents. Chapter 4 builds off the discoveries detailed within the previous chapter. Efforts to optimize the preliminary amide series from Chapter 3 are described, leading to a significant enhancement in activity. Additionally, Chapter 4 describes a synthetic breakthrough which greatly enhanced the speed of synthesis and complexity of the designed pterin inhibitors. Building upon the goal to map the RTA active site, a description of various peptide conjugated pterins is provided, as well as efforts to arrive at optimized isosteres of the most promising peptide derivatives. / text

This thesis is concerned with the synthesis and reactions of functionalised 3- liydroxypyridines, in particular 2-aryl- and 2-heteroary 1-3-liydroxypyridines by non- coupling methodology, from furan precursors. Chapter 1 reviews the synthesis and reactions of 3-hydroxypyridines. Chapter 2 describes the synthesis of 2-acylfurans via differing methods, which include acylation of the furan nucleus, Grignard reactions of furaldehydes and, most notably, reaction of lithiofurans with reagents containing a nitrile component. Chapter 3 concerns reaction of acylfurans with ammonia at high pressure and temperature to produce 3-hydroxypyridines. We have found that this ring expansion is able to withstand many differing substituents including bromine. Further development of the pyridine ring system involves reaction of the ring atoms or substituents, including protection of the hydroxy group. This ring expansion was used in the development of a novel azabenzotriazole starting from a simple furan compound, and this is reported in Chapter 4.The methodology described in this thesis is versatile and has allowed access to a range of novel pyridine derivatives in synthetically useful quantities which should be of interest in many areas of organic chemistry.

Novel indolo-macrocycles have been generated from the attempts to synthesise bis-indolo-cyclotriveratrylenes by the condensation of I, I'-diindolyl-3,3'-dimethanols catalysed by p-toluenesulfonic acid. The addition of substituents on indoles led to enhanced solubilities of the macrocycles. Nine- and six-membered ring compounds have been synthesized from the acid-catalysed reaction of I,I'-diindolyl compounds and aryl aldehydes. Some reactions of these compounds and the attempted synthesis of 2,2' diindolylmethanes from the cyclic compounds have also been described. The electrophilic substitution reactions of 3-substituted 4,6-dimethoxyindole 2,6-dimethanols and 3-substituted 4,6-dimethoxyindole-7 and 2-carbaldehydes and I-substituted indoles afforded triindolyl dialdehydes. The wriation of substituents at C-7 of indole-7-aldehydes and at C-2 of indole-2-aldehydes has also been discussed. Reaction of the hydroxymethylindole and 1,2-di(indol-I-ylmethyl)benzene gave a new macrocycle. Substitution reactions of 2,2???-diindolylmethane-7,7'-dimethanol and indole-7- and 2-aldehydes gave tetraindolyl dialdehydes. Sodium borohydride reduction of tri- and tetra-indolyl dialdehydes gave tri- and tetra-indolyl dimethanols respectively. Acid-catalysed reactions of tri- and tetra-indolyl dimethanols afforded only calix[3] and [4]indoles respectively when all substituents at C-3 of indoles were aryl groups. New conditions for indole based imine synthesis have been established Macrocyclic imine formation from mono-, di-, tri and tetra-indolyl dialdehydes has been investigated. Reactions of indole-3, 7-dialdehydes and short chain diamines (1,2-diaminoethane, 1,2-diaminobenzene and 1,6-diaminohexane) gave mixtures while the reactions with long chain diamines (1,10 diaminodecane and 1,12-diaminododecane) gave monoindolyl macrocyclic imines. Reaction of indole-2, 7-dialdehydes and short chain diamines afforded diindolyl macrocyclic imines with head-tail structures, and the 2,7';2',2";7",2'''-Tetraindole-7 ,7"'-dialdehyde underwent cyclisation with triindolyl dialdehydes and 1,6-diaminohexane afforded triindolyl macrocyclic imines. 1,2 diaminoethane while the 2,3 ';1',1 ";3 ",2"'-tetraindole-7,7"'-dialdehydes underwent imine, with its precise structure established by X-ray crystallography. Reaction of of 1,3-di(indol-l-ylmethyl)benzene and 1,2 diaminoethane yielded a new macrocyclic reactions with long chain diamines yielded monoindolyl macrocyclic imines. Reaction ring closure with 1,2 diaminoethane and 1,6-diaminohexane.

Thesis (Ph.D.) -- University of Western Sydney, 2003. / "A thesis submitted in partial fulfilment of the requirements of the degree of Doctor of Philosophy , University of Western Sydney, Campbelltown, February 2003". Includes references : leaves 188 - 200, and appendices.

Chapter 1 describes an introduction to the area of organocatalysis and delineates previous work within the Smith group on the use of isothioureas in asymmetric catalysis. Chapter 2 showcases a one-pot isothiourea-catalysed Michael addition-lactamisation using cheap and readily available starting materials (carboxylic acids) and easily prepared α,β-unsaturated ketimines via an ammonium enolate intermediate to give dihydropyridinones with high diastereo- and enantioselectivity (typically >90:10 dr, up to 99% ee). The resultant dihydropyridinones can be successfully derivatised into multiple products without erosion of stereointegrity. In chapter 3 the same concept has also been applied to the synthesis of planar molecules by using (phenylthio)acetic acid as a suiTable ammonium enolate precursor. Generation of an ammonium enolate using an achiral isothiourea (DHPB) and reaction with α,β-unsaturated trifluoromethyl ketones allows an isothiourea-mediated Michael addition / lactonisation / thiophenol elimination cascade reaction for the formation of 4,6-disubstituted and 3,4,6-trisubstituted 2-pyrones in good to excellent yields (61-99%). Notably this method allows low catalyst loadings of 1% to be used. The methodology has successfully been applied to the synthesis of a COX-2 inhibitor and a wide range of derivatisations has been performed, giving valuable aromatic and heteroaromatic products containing the trifluoromethyl motif. In chapter 4 a novel N- to C-sulfonyl migration of dihydropyridinones via photoisomerisation is investigated. The scope and limitations of this process is investigated and the process is shown to proceed without compromising the diastereo- or enantiomeric purity of the starting material, giving 5-sulfonyl products in good to excellent yields (67-95%). Mechanistic crossover has indicated that this migration includes an intermolecular step, while EPR studies provided evidence of its radical nature.