Design and synthesis of new monoterpenoid derived ligands for asymmetric catalysis /

The work to be presented herein illustrates several important facts. First, the synthesis of BIBOL (19), a 1,4-diol derived from the monoterpene camphor has allowed us to demonstrate that oxidative dimerizations of enolates can, and do proceed with nearly complete diastereoselectivity under kinetically controlled conditions. The yield of BIBOL is now 50% on average, with a 10% yield of a second diastereomer, which is likely the result of a non-kinetic hydride reduction, thereby affording the epimeric alcohol, 20, coupled on the exo face of camphor. This implies the production of 60% of a single coupling diastereomer. No other diastereomers from the reduction were observed. The utility of BEBOL has been illustrated in early asymmetric additions of diethylzinc to aryl aldehydes, with e.e.'s as high as 25-30%. '^' To further the oxidative coupling work, the same methodology which gave rise to BIBOL was applied to the chiral pool ketone, menthone. Interestingly, this gave an excellent yield of the a-halohydrin (31), which is the result of a chlorination of menthone. This result clearly indicates the high stereoselectivity of the process regardless of the outcome, and has illustrated an interesting dichotomy between camphor and menthone. The utility of the chlorination product as a precursor other chiral ligands is currently being investigated. > ' Finally, a new series of 1,3-diols as well as a new aminoalcohol have successfully been synthesized from highly diastereoselective aldol/mannich reactions. Early studies have indicated their potential in asymmetric catalysis, while employing pi-stack interactions as a means of controlling enantioselective aldol reactions.

Isolation and characterization of the female sex pheromone of the sugar beet cyst nematode, heterodera schachtii, and an analysis of male precopulatory behaviour /

The sugar beet cyst nematode, Heterodera schachtii, is a major agricultural pest. The disruption of the mating behaviour of this plant parasite in the field may provide a means of biological control, and a subsequent increase in crop yield. The H. schachtii female sex pheromone, which attracts homospecific males, was collected in an aqueous medium and isolated using high performance liquid chromatography. Characterization of the male-attractive material revealed that it was heat stable and water soluble. The aqueous medium conditioned by female H. schachtii was found to be biologically active and stimulated male behaviour in a concentration dependent manner. The activity of the crude pheromone was specific to males of H. schachtii and did not attract second stage juveniles. Results indicated that vanillic acid, a putative nematode pheromone, is not an active component of the H. schachtii sex pheromone. Male H. schachtii exhibited stylet thrusting, a poorly understood behaviour of the male, upon exposure to the female sex pheromone. This behaviour appeared to be associated with mate-finding and was used as a novel indicator of biological activity in bioassays. Serotonin, thought to be involved in the neural control of copulatory behaviour in nematodes, stimulated stylet thrusting. However, the relationship between stylet thrusting induced by the sex pheromone and stylet thrusting induced by serotonin is not clear. Extracellular electrical activity was recorded fi-om the anterior region of H. schachtii males during stylet thrusting, and appeared to be associated with this behaviour. The isolation of the female sex pheromone of H. schachtii may, ultimately, lead to the structural identification and synthesis of the active substance for use in a novel biological control strategy.

The Synthesis of Imidazole Fatty Acid Conjugates as Inhibitors of Apoptosis

Ionizing radiation is known to initiate apoptosis in mammalian cells by causing the transformation of cytochrome c into a peroxidase, which results in the specific peroxidation of the mitochondrial phospholipid cardiolipin. Here we report the design and synthesis of 8 imidazole fatty acid derivatives that bind to the cyt c:CL complex and inhibit the peroxidase activity required for the initiation of apoptosis. We postulate that imidazole acts as a sixth ligand to the haem iron and stops the interaction with H2O2. Two mitochondrially directed analogues (3-hydroxypropyl)triphenylphosphonium esters) of 12-imidazole-stearic acid and 12-imidazole-oleic acid not only were demonstrated to be peroxidase inhibitors in vitro, but were also extraordinarily effective in protecting mice from lethal doses (9 Gy) of ionization radiation. We studied the structure activity relationship to a group of triphenyl phosphonium derivatives containing imidazole at different positions on the fatty acid chain, and observed that the C8-imidazole stearate analogue had marginally better activity than the others. But overall, the structure activity result were remarkable “flat” with all compounds prepared having rather similar inhibitory strength. We also synthesized carnitine mono and di-esters of 12-imidazole fatty acids but full biological data is not yet available for these compounds.

Reactions of some non-enolisable chloroketones with amide ion and a new synthesis of acridones /|nGuo-shyoung John Chen. -- 260 St. Catharines, Ont. : [s. n.],

This research was directed mainly towards the investigation of the reacti.ons of· substituted chlorobenziophenones under strongly basi,c conditions. The work 'can be divided into two main sections. The Introduction deals mainly with historical studies on aryne chemistry and the Haller-Bauer reaction. Secti.on I i.s concerned with syntheses of 2-benzamido-2'chlorobenzophenone and 2-benzamido~3'-chlorobenzophenone,and with thei,r respective reactions wi.th potassium amide in ammonia. o-Chlorophenylacetic acid was converted to the acid chloride and then by Friedel-Craftsreaction with benzene to w-(o-chlorophenyl)acetophenone. Reaction wi.th phenylhydrazine and Fischer cyclization gave 3- (0chlorophenyl)- 2-phenylindole, which was ozonized to 2-benzamido-2'chlorobenzophenone. The isomeric 3' -chlor,..o ke: tone was similarly synthesised from m-chlorophenylacetic acid. Both the 2'- and 3' -ch.loroketones gave N-benzoylacridone on treatment with potassium amide in ammonia; an aryne mechanism is involved for the 3'-chloroketone but aryne and nucleophilic substitution mechanisms are possible for the 2'-chloroketone. Hydrolysis of the 2'- and 3'-chloroketones gave 2-amino-2'chlorobenzophenone and 2-amino-3'-chlorobenzophenone respectively. A second new acridone synthesis is given in the Appendix involving reactions of these two ketones with potassium t-butoxide in t-butylbenzene. i Section 2 deals with the investigation of the reaction of some tricyclic ch1orobenzophenones with potassium amide in liquid ammonia. These were 1-ch1orof1uorenone; which was pr~pared in several steps from f1uoranthene, and 1- and 2-ch1oroanthraquinones. 1-Ch1orof1uorenone gave 1-aminof1uorenone ; 1-ch1oroanthraquinone gave 1- and 2-aminoanthraquinones; 2-ch1oroanthraquinone was largely recovered from the attempted reaction.

Chemoenzymatic Total Synthesis of Morphine alkaloids: Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen Strategy and ent-Hydromorphone via an Oxidative Dearomatization/intramolecular [4+2] Cycloaddition

This thesis describes the chemoenzymatic synthesis of three morphine alkaloids. The total synthesis of dihydrocodeine and hydrocodone was accomplished starting from bromobenzene in 16 and 17 steps, respectively. The key steps included a microbial oxidation of bromobenzene by E. coli JM109 (pDTG601A), a Kazmaier-Claisen rearrangement of glycinate ester to generate C-9 and C-14 stereo centers, a Johnson-Claisen rearrangement to set the C-13 quaternary center, and a C-10/C-11 ring closure via a Friedel-Crafts reaction. In addition, the total synthesis of ent-hydromorphone starting from β-bromoethylbenzene in 12 steps is also described. The key reactions included the enzymatic dihydroxylation of β-bromoethylbenzene to the corresponding cis-cyclohexadienediol, a Mitsunobu reaction, and an oxidative dearomatization followed by an intramolecular [4+2] cycloaddition.

High-Spin and Emissive Molecular Materials: Synthesis and Characterization of New Polynuclear Ni(II) Complexes from the Use of Aromatic Schiff Bases as Bridging Ligands

The employment of the bridging/chelating Schiff bases, N-salicylidene-4-methyl-o-aminophenol (samphH2) and N-naphthalidene-2-amino-5-chlorobenzoic acid (nacbH2), in nickel cluster chemistry has afforded eight polynuclear Ni(II) complexes with new structural motifs, interesting magnetic and optical properties, and unexpected organic ligand transformations. In the present thesis, Chapter 1 deals with all the fundamental aspects of polynuclear metal complexes, molecular magnetism and optics, while research results are reported in Chapters 2 and 3. In the first project (Chapter 2), I investigated the coordination chemistry of the organic chelating/bridging ligand, N-salicylidene-4-methyl-o-aminophenol (samphH2). The general NiII/tBuCO2-/samphH2 reaction system afforded two new tetranuclear NiII clusters, namely [Ni4(samph)4(EtOH)4] (1) and [Ni4(samph)4(DMF)2] (2), with different structural motifs. Complex 1 possessed a cubane core while in complex 2 the four NiII ions were located at the four vertices of a defective dicubane. The nature of the organic solvent was found to be of pivotal importance, leading to compounds with the same nuclearity, but different structural topologies and magnetic properties. The second project, the results of which are summarized in Chapter 3, included the systematic study of a new optically-active Schiff base ligand, N-naphthalidene-2-amino-5-chlorobenzoic acid (nacbH2), in NiII cluster chemistry. Various reactions between NiX2 (X- = inorganic anions) and nacbH2 were performed under basic conditions to yield six new polynuclear NiII complexes, namely (NHEt3)[Ni12(nacb)12(H2O)4](ClO4) (3), (NHEt3)2[Ni5(nacb)4(L)(LH)2(MeOH)] (4), [Ni5(OH)2(nacb)4(DMF)4] (5), [Ni5(OMe)Cl(nacb)4(MeOH)3(MeCN)] (6), (NHEt3)2[Ni6(OH)2(nacb)6(H2O)4] (7), and [Ni6(nacb)6(H2O)3(MeOH)6] (8). The nature of the solvent, the inorganic anion, X-, and the organic base were all found to be of critical importance, leading to products with different structural topologies and nuclearities (i.e., {Ni5}, {Ni6} and {Ni12}). Magnetic studies on all synthesized complexes revealed an overall ferromagnetic behavior for complexes 4 and 8, with the remaining complexes being dominated by antiferromagnetic exchange interactions. In order to assess the optical efficiency of the organic ligand when bound to the metal centers, photoluminescence studies were performed on all synthesized compounds. Complexes 4 and 5 show strong emission in the visible region of the electromagnetic spectrum. Finally, the ligand nacbH2 allowed for some unexpected organic transformations to occur; for instance, the pentanuclear compound 5 comprises both nacb2- groups and a new organic chelate, namely the anion of 5-chloro-2-[(3-hydroxy-4-oxo-1,4-dihydronaphthalen-1-yl)amino]benzoic acid. In the last section of this thesis, an attempt to compare the NiII cluster chemistry of the N-naphthalidene-2-amino-5-chlorobenzoic acid ligand with that of the structurally similar but less bulky, N-salicylidene-2-amino-5-chlorobenzoic acid (sacbH2), was made.