Graduation date: 1998

Graduation date: 1995

Endophytic fungi (A. coenophialum and A. lolii) which infect grasses produce ergot alkaloids that serve as the grasses' chemical defenses and enhance the vigor of the grass. Turf-type tall fescue with high endophyte levels has been deliberately developed to produce a greener, more vigorous, pest-resistant turf. Consumption of endophyte-infected grass causes various toxicity symptoms in livestock. Cattle in the southeastern and midwestern United States, where tall fescue is grown on 14 million hectares, often develop signs of toxicosis during summer months from grazing plants in fected by A. coenophialum. A more severe form of the disease, fescue foot, has been associated with cold environment and reported in late fall and winter months not only in the southeastern United States but also in the northwest United States. In New Zealand, where perennial ryegrass is grown on 7 million hectares of pasture, sheep often develop a condition called ryegrass staggers from grazing plants infected by A. lolii. New Zealand reports economic losses grazing plants infected by A. lolii. New Zealand reports economic losses associated with the sheep industry of $205 million per year. In the United States, economic losses associated with the beef cattle industry alone is estimated at $600 million per year. Range finding experiments and case studies of fescue foot and perennial ryegrass staggers (PRGS) were conducted on cattle and sheep under grazing and barn conditions. The main objective was to determine threshold levels of the endophyte toxins, ergovaline (EV) (appendix 1) and lolitrem B (appendix 2), associated with the diseases of fescue foot and PRGS respectively. Fescue foot was experimentally induced in cattle under barn studies in the spring with 825 ppb ergovaline. The ergovaline contaminated feed was given for a period of 42 days. Similar barn studies in sheep in spring to early summer did not produce clinical fescue foot with up to 1215 ppb. Field studies of natural fescue foot in a herd of sheep were conducted, (ie 540 ppb) values of ergovaline in the feed, but clinical disease was not produced in late fall through winter. A case study from a herd of sheep revealed 813 ppb dietary ergovaline had produced fescue foot in the months of fall (November). Fields of perennial ryegrass (PRG) where sheep received 2,135 ppb lolitrem B toxin were associated with clinical cases of PRGS in 42 sheep of 237 sheep (18 percent incidence rate) in the Willamette Valley of Oregon. Three months later, sheep on this same field which then had 1,465 ppb lolitrem B, did not have PRGS. These were the first range finding experiments undertaken in this locale to document threshold levels of endophyte toxins associated with fescue foot and PRGS. / Graduation date: 1994

Intramolecular hydroamination represents a potentially general, simple strategy to access various nitrogen heterocycles. While important progress has been accomplished in recent years, six-membered ring formation via alkene hydroamination is typically difficult and limited to terminal alkenes, suggesting that only 2-methylpiperidines can be accessed reliably with current methods. As part of the Beauchemin group efforts on metal-free concerted hydroamination methods, the first part of this thesis describes the development of a Cope-type hydroamination-Meisenheimer rearrangement (CHMR) sequence that is applicable in inter- and intramolecular reactions. Data acquired from optimization on a difficult substrate (coniine) and the successful application of the CHMR sequence to the syntheses of N-norreticuline and 10-desbromoarborescidine are reported. The amination of alkenes is surprisingly scarcely used in the synthesis of complex alkaloids despite its potential for the construction of structurally challenging molecules while avoiding functional group interconversions. Hence, the second part of this thesis describes the studies on a novel amination sequence, consisting of an intermolecular Diels-Alder followed by an intramolecular hydroamination reaction, in the efforts towards the synthesis of biologically active and structurally complex Manzamine A. As such, the synthesis of the model substrates, including the development of a novel family of aminodienes, as well as the assessment of their reactivity towards [4+2] cycloadditions is reported.

Tetrahydroisoquinoline alkaloids are a class of structurally complex natural products and a huge number of its natural product widely exist in nature which, from the discovery has been more than a century, it compounds with high anti-tumor activity, antibacterial and other physical activity, but also because of its special structure, with low oncentration of biological activity, but these alkaloids are not sold in the market mainly due to a less natural extraction, chemical synthesis method and multi-step, low yield. Therefore, we constructed a combination of tetrahydroisoquinoline alkaloids and the pyrazino [2,1-b] quinazoline-3,6-diones structure of the new compounds, which have the quinazolinone compounds which is the drug synthesis and drug activity on the bond, is also a kind of unique and widely used drug structure, and causes a lot of scientists and drug research interest and discussion, as we develop the motivation.

The tetrahydroisoquinoline alkaloids have been studied thoroughly about their biological and chemical significance over the past 30 years. These natural products show great biological activity, especially ET-743 and saframycin A, makes them promising therapeutics, while their structural complexity and particularity provide challenging synthetic targets. These alkaloids or derivatives show interesting biological activity, but the most important drawback as potential market therapeutics is the minute amount of them available from nature, and the synthetic methods published are inconvenient, difficult, and hard to handle. Herein is described our researches about the tetrahydroisoquinoline alkaloids. Chapter 1 describes relevant background related to the biological significance of these alkaloids, and the currently synthetic studies toward these natural products. Chapter 2 describes our design and synthesis of the analogues based on the anticancer mechanism of the tetrahydroisoquinoline alkaloids, and the biological activities of these analogues. Chapter 3 describes a rapid synthetic route for the common structure of the bis-tetrahydroisoquinoline alkaloids via a controlled mono-Pictet-Spengler cyclization.

Social parasitism, the exploitation of a society by other social organisms, has evolved independently numerous times within social animals. In this thesis, I integrate behavioral, evolutionary and chemical analyses to elucidate the evolution of social parasitism in Megalomyrmex ants. I examine host-parasite interactions in two Megalomyrmex species, identify venom alkaloids, and reconstruct the phylogenetic relationships between species. In Chapter 1, I analyze nest architecture and behavioral interactions between the ant host Cyphomyrmex cornutus and its parasite Megalomyrmex mondabora. This is the first detailed account of the natural history of this host and its social parasite. In Chapter 2, I report a one-year-long fitness experiment that tests whether Trachymyrmex cf. zeteki colonies suffer reduced fitness from an association with the social parasite Megalomyrmex symmetochus. I show that M. symmetochus parasites negatively impact host fitness though several mechanisms, including a) manipulation of the host worker grooming behavior; b) castration of host queens produced by the host colony, which then become workers; and c) reduction of garden size, host worker number, and host reproductive output. In Chapter 3, I determine that five venom alkaloids of Megalomyrmex are taxonomically informative to help differentiate cryptic species within the M. mondabora complex; new species in this complex need to be described in a future taxonomic revision. In Chapter 4, I reconstruct phylogenetic relationships of the genus Megalomyrmex with DNA sequence information. I conclude that the genus is monophyletic and corroborate two of the four species groups proposed by Brandão (1990) in a previous morphological revision. I also find evidence in support of Darwin’s Predation Hypothesis on the origin of social parasitism, which postulates that socialparasitic behaviors evolve from predatory behaviors. Lastly, I discuss promising future research directions on the evolution of social parasitism in the ant genus Megalomyrmex, which could serve as a model for the study of social parasitism in other lineages of social insects. / text

A novel application of the Pauson-Khand reaction was applied to the synthesis of a series of bridged azatricyclic piperazines. This method represents the first application of the Pauson-Khand reaction to synthesize azabridged scaffolds. The ubiquity of bridged azabicyclic ring systems in biologically active natural product skeletons has provided the synthetic chemist with a wealth of opportunity for development over the last century. To this day, the development of new methodologies to tackle these structurally challenging systems remains at the forefront of synthetic chemistry. During our efforts to achieve a total synthesis of the stemofoline alkaloids, we have thus far developed a novel and scalable synthetic strategy to access the fully functionalized caged azatricyclic core of these challenging alkaloids. The overall synthetic strategy we have implemented began with the commercially available and affordable 2-deoxy-D-ribose as a chiral starting material. Furthermore, we have developed a novel 1,3-dipole cascade cycloaddition, which was successfully employed as the key step in the construction of the bridged azatricyclic core of the stemofoline alkaloids. / text

Herein is described our synthetic studies towards the synthesis of secu'amamine A, a member of the Securinega alkaloids. The first chapter describes the isolation, biological significance and previous synthesis of secu'amamine A. Chapter 2 discusses our proposed biogenetic origin of secu'amamine A from allosecurinine and the model studies to support the intermediacy of the putative aziridinium ion. Chapter 3 discusses our synthetic approach to the formation of rings A and C, as well as investigations on the regioselective functionalization of 1,2-dihydropyridines. Chapter 4 discusses the synthesis of ring D from ring D' and the transformations of our advanced intermediates with different carbamate protective groups. Chapter 5 consists of experimental details and characterization data for all new compounds. / text

Lupin seed has the potential to be used as a protein supplement in ruminant rations, but its usage is restricted by the presence of alkaloids. Experiments were conducted with the aim of determining whether the removal of specific toxic alkaloids, lupanine and 13-hydroxylupanine, from crushed lupin seed (CLS) would improve the organic matter intake (OMI) and average daily gains (ADG) in lambs, and also improve the lactation performance in dairy cows. Effects on liver function in lambs were also investigated. An additional study on the effects of the detoxification of CLS on the degradation of protein was conducted. In Experiment 1, 30 growing Corriedale lambs were fed five diets for 105 d according to a randomized complete block design (RCBD) with six blocks. Two diets contained intact CLS at 15% (LUI-15) or 30% (LUI-30) of DM; two other diets contained detoxified CLS at 15% (LUD-15) or 30% (LUD-30) and the control (CON) diet was supplemented with crushed sunflower seed, which was locally prepared, on-farm. All diets were formulated to be isonitrogenous (16% CP). The alkaloid content (lupanine and 13-OH lupanine) of the diets was.31,.70,.21 and.52% for LUI-15, LUI-30, LUD-15 and LUD-30, respectively. Thus, diets containing detoxified CLS contained approximately 30% less alkaloids than those with intact CLS. Estimates of ADG of lambs fed diets containing detoxified CLS was higher (P $<$.01) (120 g.d$ sp{-1}$) than that of lambs fed intact CLS (76 g.d$ sp{-1}$). The OMI (73 g/Wkg$ sp{0.75}$) was also higher, although not significantly, for lambs fed diets containing detoxified CLS. Feed conversion efficiency was increased (P $<$.05) by the detoxification of CLS. Lambs fed diets containing intact CLS consumed more OMI as time progressed, suggesting that adaptation to CLS might have occurred. Lambs fed diets containing intact CLS demonstrated increased trends in the activity in plasma of the enzymes glutamic oxaloacetic transferase (GOT) and $ gamma$-glutamyl transfer