The [2,3]-sigmatropic rearrangement is a pericyclic reaction of great synthetic utility to organic chemists. Within the scope of this reaction exist some cases in which the product corresponding to a [1,2] rearrangement is formed, despite the fact this is a forbidden process. Generally this is explained by a radical dissociation-recombination pathway; however, studies into the failure of transition state theory and the necessity to incorporate dynamic effects into mechanistic theory lead us to believe such products may arise from these phenomena. In particular, the possibility that many of these products result from an “unsymmetrical bifurcating surface” in the potential energy landscape is intriguing. To investigate this possibility, the Sommelet-Hauser rearrangement of N-allyl-N,N-dimethylglycine methyl ester was explored. The combined use of experimental and theoretically predicted kinetic isotope effects (KIEs) has been previously shown to deliver great mechanistic insight into reactions. The combination of these techniques, however, has found little employ in studying [2,3] rearrangements. This combination was used to study this reaction, using the Singleton method for determining small heavy-atom isotope effects. Resulting experimental KIEs suggest the reaction proceeds by an asynchronous, concerted, early transition state, and is relatively exothermic. This agrees with previous studies and Hammond’s postulate. Predicted theoretical KIEs are in good agreement with experimental KIEs, and the associated transition structure confirms the results suggested by experiment. Interestingly, as calculations proceed from gas phase to solvent models, the activation barrier of the reaction increases, while its exothermicity decreases. The energy difference determined between the lowest and second lowest energy transition structures decreases to 0.81 kcal/mol in the PCM model, so we cannot exclude the contribution of this transition structure to the reaction. However, qualitative results from the associated KIEs and energetics are consistent with the lowest energy transition structure. This reaction does not seem to afford the [1,2] product, and most likely dynamic effects are insignificant in determining product distribution. However, the study has validated, with respect to this body of reactions, both the use of the Singleton method for KIE determination and the combination of these experimental and theoretical techniques.

Additions of carbon-centered radicals to alkenes are useful method for cyclic compounds formation. Manganese(III)-based oxidative free-radical cyclizations, where the radicals are generated and terminated oxidatively, are established as efficient methods for the construction of cyclic molecule. Treatment of a mixture of dimedone, Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid with homobenzonorbornadiene (80) (4h at 50 &amp / #61616 / C) gave furan derivative (107), dihydrofuran adduct (108), in addition to rearranged product (109) as a major product. The reaction run under the same reaction conditions without using Cu(II)acetate for 8h afforded dihydrofuran adduct (108) along with dihydrofuran (110), where no rearranged products could be formed. On the other hand, reflux of alkene 80 with a mixture of acetylacetone, Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid (3h at 50 &amp / #61616 / C) gave oxidative product (131) and rearranged product (132) (major). The reaction run under the same reaction conditions without using Cu(II)acetate for 7h produced, in addition to the oxidative product 131, a dihydrofuran derivative (133). In a second system, we examined the oxidation of benzobarrelene 82 with Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid (1h at 50 &amp / #61616 / C) in presence of dimedone resulted in the formation of five different products rearranged products (148, 149) and a dihydrofuran (109), besides, a mixture containing two major rearranged isomers (150/151). The same reaction was carried out under the same conditions in absence of Cu(II) for 9h and gave the isomeric mixture 150/151 exclusively, and the yield was reduced. The oxidative cyclization of acetylacetone with alkene 82 for 3h at 50 &amp / #61616 / C, afforded in addition to the dihydrofuran (132), two rearranged products (169, 170) and a mixture consisting of two isomers (171/ 172). The isomeric mixture was converted to one product by treatment with methanolic ammonia providing hydroxyl derivative which was oxidized by MnO2 to afford product 174 in a good yield. Additionally, we investigated the behavior of nitrogen bridge in the bicyclic system on the course of the reaction. Oxidation of N-carbethoxy-7-aza-2,3-benzonorbornadiene 83 with dimedone in the presence of Cu(OAc)2 as well as in its absence in glacial acetic acid (2h at 50 &amp / #61616 / C), rearranged product (189) was obtained as the sole product. Regarding the reaction of aza-derivative 83 with acetylacetone in the presence of Cu(OAc)2 (18 h at 50 &amp / #61616 / C), rearranged product 195 was resulted as sole product. The reaction of 83 was also run with out Cu(OAc)2 for 22h and gave the rearranged product 195.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 106-115).

A summary of research conducted since September 2007 at the University of Toronto in the laboratory of Professor Robert A. Batey is presented in this thesis, which is divided into four chapters. The first chapter contains a two-part introduction, where aryl- and aliphatic-Claisen rearrangements are discussed in part 1, and the nucleophilic addition of organoboron reagents to unsaturated C–N functionalities is described in part 2. Chapter 2 contains research involving synthetic and theoretical studies of aryl-Claisen rearrangements and other sigmatropic reactions. The work towards developing the lanthanide-catalyzed domino aryl-Claisen rearrangement for the synthesis of contiguous aryl–C(sp³) moieties is presented first. This is followed by computational studies involving E/Z-selectivity differences for the aryl-Claisen rearrangement, which was an issue noted for the domino aryl-Claisen reaction of a linear substrate. The mechanistic origins of E/Z-selectivity differences for the mono aryl-Claisen rearrangement, which was experimentally ambiguous for over 40 years, is resolved through computational methods. A theoretical analysis of selectivity differences for the allylic azide rearrangement is also described. The third section contains a discussion of Eu(fod)3-catalyzed aryl-Claisen rearrangements on vinyl bromide systems and preliminary studies involving application of the substrates in cross-coupling reactions, and other attempted mono- and domino sigmatropic rearrangements are presented in the fourth section. In chapter 3, the search for computational methods that can accurately predict experimental free energy of activation barriers for the aliphatic-Claisen rearrangement through benchmarking studies with a priori kinetic barrier and kinetic isotope effect data is described. Methods were found to predict new valid transition states and predict ΔG‡ values with a mean unsigned error of 0.3 kcal/mol relative to experimental values. In chapter 4, the development of new allylboration reaction is outlined, involving the double allylboration of nitriles and anhydrides, and initial studies towards the first aminoallylboration reactions of N-aluminoaldimines to form 1,2-diamines.

Invasive growth through a substrate requires a massive amount of penetrative force, and this is generated in the space of a few microns in a growing tip. This process is known to be critical in the root hair, pollen tube, rhizoids, and the topic of this thesis, hyphal growth. However defining the mechanisms underlying the tip growth remains a contentious issue. Shortcomings in control of direction and regulation of growth began to undermine early turgor-based theories, and the cytoskeletal protein actin, ubiquitous in nature and with crucial roles in structure and motility became a target for investigation. A major breakthrough came with the discovery that a characteristic actin depleted zone (ADZ) occurs at the growing tip of hyphae during invasive but not non-invasive hyphal growth. The ADZ is likely to have an important role in generating the greater protrusive force required for invasive growth. However, since its discovery, little has been determined about the characteristics of the ADZ. Uncertainty in the description of the physical environment the hyphae face adds a layer of complexity to interpretation of results. This thesis aims to address this issue, studying the impact of increasing agarose substrate concentration on the presence and dimensions of the ADZ in the oomycete A. bisexualis. Furthermore, agarose is examined by compression and imaging to compare the physical characteristics of the agar samples over the range of concentrations, and determine whether increasing agarose concentration influences agarose gel structure. Results suggest a difference in the number of ADZ observed in non-invasive compared with invasive samples, however no significant differences in the number or dimensions of ADZ were found amongst the 1-4% w/v agarose concentrations. The 0% sample showed 20.7 percent of hyphae exhibited depleted zones, while 1, 2, 3 and 4% samples showed 56.9%, 48.8%, 40.9% and 54.2% respectively. ADZ dimensions did not correlate with agarose concentration. The average ADZ area:hyphal diameter ratio was 0.634, 0.526, 0.430, 1.09, and 0.65 for 0-4% agarose concentrations respectively. Additionally, investigation of gel compression forces revealed gel strength increases with agarose concentration. The force required to compress the agarose increased from 1.85 Psi in 1% agarose to 4.85, 7.09 and 12.22 Psi in 2, 3 and 4% agarose concentrations respectively. SEM imaging, however, suggests heterogeneity of the fibrous interconnected network of agarose gels at a microscopic scale with variable porous structure at all agarose concentrations. This scale is relevant to hyphal tip growth. In combination, these results suggest F-actin depletion may be a response mechanism to provide greater force for invasive growth. Additionally, this response is not dependent on the concentration of the agarose media, possibly due to the variability encountered within the media. These results contribute another important step forward in unraveling the elusive mechanism of tip growth.

Die Nitron-Cycloaddition an ein dearomatisiertes Phenol ermöglichte den leichten Aufbau des Phenanthrengerüstes von Codein in der gewünschten Konfiguration. Weitere Schritte führten mit kompletter Diastereoselektivität zu Allopseudocodein und nach Allylverschiebung durch Hydrolyse der Chlorcodide schließlich zu (±)-Codein.

Invasive growth through a substrate requires a massive amount of penetrative force, and this is generated in the space of a few microns in a growing tip. This process is known to be critical in the root hair, pollen tube, rhizoids, and the topic of this thesis, hyphal growth. However defining the mechanisms underlying the tip growth remains a contentious issue. Shortcomings in control of direction and regulation of growth began to undermine early turgor-based theories, and the cytoskeletal protein actin, ubiquitous in nature and with crucial roles in structure and motility became a target for investigation. A major breakthrough came with the discovery that a characteristic actin depleted zone (ADZ) occurs at the growing tip of hyphae during invasive but not non-invasive hyphal growth. The ADZ is likely to have an important role in generating the greater protrusive force required for invasive growth. However, since its discovery, little has been determined about the characteristics of the ADZ. Uncertainty in the description of the physical environment the hyphae face adds a layer of complexity to interpretation of results. This thesis aims to address this issue, studying the impact of increasing agarose substrate concentration on the presence and dimensions of the ADZ in the oomycete A. bisexualis. Furthermore, agarose is examined by compression and imaging to compare the physical characteristics of the agar samples over the range of concentrations, and determine whether increasing agarose concentration influences agarose gel structure. Results suggest a difference in the number of ADZ observed in non-invasive compared with invasive samples, however no significant differences in the number or dimensions of ADZ were found amongst the 1-4% w/v agarose concentrations. The 0% sample showed 20.7 percent of hyphae exhibited depleted zones, while 1, 2, 3 and 4% samples showed 56.9%, 48.8%, 40.9% and 54.2% respectively. ADZ dimensions did not correlate with agarose concentration. The average ADZ area:hyphal diameter ratio was 0.634, 0.526, 0.430, 1.09, and 0.65 for 0-4% agarose concentrations respectively. Additionally, investigation of gel compression forces revealed gel strength increases with agarose concentration. The force required to compress the agarose increased from 1.85 Psi in 1% agarose to 4.85, 7.09 and 12.22 Psi in 2, 3 and 4% agarose concentrations respectively. SEM imaging, however, suggests heterogeneity of the fibrous interconnected network of agarose gels at a microscopic scale with variable porous structure at all agarose concentrations. This scale is relevant to hyphal tip growth. In combination, these results suggest F-actin depletion may be a response mechanism to provide greater force for invasive growth. Additionally, this response is not dependent on the concentration of the agarose media, possibly due to the variability encountered within the media. These results contribute another important step forward in unraveling the elusive mechanism of tip growth.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on July 1, 2010). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 139-193).

Cancer development is driven by somatic genome alterations, ranging from single point mutations to larger structural variants (SV) affecting kilobases to megabases of one or more chromosomes. Studies of somatic rearrangement have previously been limited by a paucity of whole genome sequencing data, and a lack of methods for comprehensive structural classification and downstream analysis. The ICGC project on the Pan-Cancer Analysis of Whole Genomes provides an unprecedented opportunity to analyse somatic SVs at base-pair resolution in more than 2500 samples from 30 common cancer types. In this thesis, I build on a recently developed SV classification pipeline to present a census of rearrangement across the pan-cancer cohort, including chromoplexy, replicative two-jumps, and templated insertions connecting as many as eight distant loci. By identifying the precise structure of individual breakpoint junctions and separating out complex clusters, the classification scheme empowers detailed exploration of all simple SV properties and signatures. After illustrating the various SV classes and their frequency across cancer types and samples, Chapter 2 focuses on structural properties including event size and breakpoint homology. Then, in Chapter 3, I consider the SV distribution across the genome, and show patterns of association with various genome properties. Upon examination of rearrangement hotspot loci, I describe tissue-specific fragile site deletion patterns, and a variety of SV profiles around known cancer genes, including recurrent templated insertion cycles affecting TERT and RB1. Turning to co-occurring alteration patterns, Chapter 4 introduces the Hierarchical Dirichlet Process as a non-parametric Bayesian model of mutational signatures. After developing methods for consensus signature extraction, I detour to the domain of single nucleotide variants to test the HDP method on real and simulated data, and to illustrate its utility for simultaneous signature discovery and matching. Finally, I return to the PCAWG SV dataset, and extract SV signatures delineated by structural class, size, and replication timing. In Chapter 5, I move on to the complex SV clusters (largely set aside throughout Chapters 2—4) , and develop an improved breakpoint clustering method to subdivide the complex rearrangement landscape. I propose a raft of summary metrics for groups of five or more breakpoint junctions, and explore their utility for preliminary classification of chromothripsis and other complex phenomena. This comprehensive study of somatic genome rearrangement provides detailed insight into SV patterns and properties across event classes, genome regions, samples, and cancer types. To extrapolate from the progress made in this thesis, Chapter 6 suggests future strategies for addressing unanswered questions about complex SV mechanisms, annotation of functional consequences, and selection analysis to discover novel drivers of the cancer phenotype.