Recent theoretical developments have led to a renewed interest in the potential role of chromosomal rearrangements in speciation. Australian morabine grasshoppers (genus Vandiemenella, viatica species group) provide an excellent study system to test this potential role, because they show extensive chromosomal variation: 12 chromosomal races/species with parapatric distributions. The research in this thesis involves the application of molecular genetic analyses to examine patterns of gene introgression among chromosomal races of Vandiemenella at three different spatial scales: local-scale hybrid zone analysis, island-scale phylogeography, and continental-scale phylogeography. The aims of these multi-scale analyses are to investigate whether chromosomal races represent genetically distinct taxa with limited gene flow, and to infer the historical biogeography of Vandiemenella and evolutionary origins of their parapatric distributions. Karyotype and 11 nuclear markers revealed a remarkably narrow hybrid zone with substantial linkage disequilibrium and strong deficits of heterozygotes between the chromosome races P24(XY) and viatica17 on Kangaroo Island, suggesting that the zone is maintained by a balance between dispersal and selection against hybrids (tension zone). Selection that maintains the stable hybrid zone is unlikely to be operating only on loci linked to rearranged chromosomes. Island-scale and continental-scale phylogeography using multiple nuclear markers indicated that Vandiemenella chromosome races/species generally represent genetically distinct taxa with reduced gene flow between them. In contrast, analyses of a mitochondrial gene showed the presence of distinctive and geographically localised phylogroups that do not correspond with the distribution of the Vandiemenella taxa. These discordant population genetic patterns are likely to result from introgressive hybridization between the taxa and range expansions and contractions. Overall, our molecular analyses favour the allopatric mode of diversification for the evolution of Vandiemenella and do not support the stasipatric speciation model of White (1978). Patterns of genetic differentiation between the chromosomal races analysed at three different spatial scales show dynamic responses of the grasshoppers to past climatic fluctuations, leading to opportunities for long-term isolation and allopatric fixation of new chromosome variants and molecular mutations at many loci. Further analyses are necessary to assess potential roles of chromosomal rearrangements in facilitating diversification in Vandiemenella by reducing recombination within the rearranged chromosome segments.

The Johnson-Claisen rearrangement is a valuable method for the formation of new carbon-carbon bonds, however the rearrangement suffers from high reaction temperatures and prolonged reaction times. On the basis of previous research into substituent-induced rate enhancements of the Claisen rearrangement, we aimed to reduce the severity of the Johnson-Claisen conditions by applying this reaction to allylic cyanohydrins. Application of the standard Johnson-Claisen conditions (excess of orthoester and catalytic protic acid) to allylic cyanohydrins resulted in their decomposition to a,b- unsaturated aldehydes. The anticipated d-ethoxycarbonyl-a,b-unsaturated nitriles were formed in trace amounts. Subsequent optimisation of this reaction has allowed a practical entry into a,b- unsaturated nitriles in reasonable yields, however high reaction temperatures were necessary for an efficient conversion. Clearly, a change of approach was desired; we have since discovered that mixed orthoesters derived from allylic alcohols undergo methanol elimination in the presence of triisobutylaluminium (TIBAL) at room temperature to form mixed ketene acetals. TIBAL then promotes immediate Claisen rearrangement of these intermediates, and subsequent reduction of the ester products to yield, g,d- unsaturated primary alcohols in a convenient one-pot procedure, with yields ranging from 52-81% and with a range of functional group tolerance.

For the past years, our laboratory has been interested in the development of a specific class of functionalised orthoester derivatives and their application as annelating reagents. Previous work had demonstrated that these reagents could be used in a two-step procedure to generate interesting spirocyclic ketones. At the onset of our thesis, we devoted our efforts to the study and application of this methodology. This resulted in an improved and more efficient procedure for the spirohexannelation of â-ketoketals. During these initial studies, an intriguing and novel transannular cyclisation was discovered. The reactivity of these spirocycles was also briefly examined, laying the ground for an application to the total synthesis of Agarospirol, Hinesol and á-Vetispirene, three natural products belonging to the Spirovetivane family. The applicability of a CAN-catalysed deprotection of ketals and silyl ethers, in the presence of an enol triflate moiety, was also investigated. The potential of our functionalised orthoesters as annelating agents was then further evaluated in the context of other silyl enolethers. The heteroaromatic derivatives of furan proved to be excellent coupling partners for our functionalised orthoesters, and enabled the efficient preparation of a wide array of butenolides. These butenolides could then be elaborated, by an efficient and highly stereoselective radical-mediated cyclisation, into bicyclic lactones. Alternatively, treatment with base triggered an efficient spirocyclisation, delivering spirocyclic butenolides in good to excellent yields. The corresponding pyrrole derivative was also examinated, and preliminary work hints at the possibility of readily preparing azaspirocycles as well as indolizidine frameworks. Finally, the evaluation of silylated acyloins allowed an entry into the chemistry of cyclobutanones, and a simple procedure for the synthesis of spirocyclic ethers was developed. During these investigations, an unexpected fragmentation was serendipitously discovered upon application of the Beckmann rearrangement. We were able to use this reaction in a new procedure for the synthesis of interestingly substituted tetrahydropyrans.

Given the large number of biologically active natural products containing medium-sized ether motifs, many organic chemists have shown great interest for developing new methodologies to access these structures. In particular, numerous synthetic methodologies for the construction of seven-membered and eight-membered ethers have been developed by research groups around the world. Recent advances in the synthesis of seven-membered and eight-membered ethers will be reviewed in chapter one. This chapter will cover some of the more notable publications from the last five years (from 2005 to 2009). In chapter two, the development of ring expansion reactions via [1,2]-shift rearrangements of thioacetal-derived sulfonium ylides will be described. A variety of functionalized diazoketones and diazoketoesters were made from commercially available starting materials. Sulfur-bridged seven-membered and eight-membered ethers were constructed upon treatment of these diazo precursors with suitable metal catalysts. It was found that Rh2(OAc)4 was a better catalyst for diazoketones, while Cu(hfacac)2 proved to be more effective for diazoketoesters. This methodology provides a convenient route to the seven- and eight-membered ethers in relatively few steps. In chapter three, the methodology for construction of sulfur-bridged ethers was employed as the key step in the attempted formal synthesis of (+)-laurencin. In this approach, the relative and absolute stereochemistry was established by a highly enantioselective and diastereoselective allylboration, a facially selective Michael addition, and a thermodynamically controlled acetal formation. The eight-membered sulfur-bridged ether was efficiently constructed using our [1,2]-shift reaction of a sulfonium ylide in toluene at 100 oC in the presence of Cu(hfacac)2. The following desulfurization and decarboxylation was effective at affording an advanced intermediate in this synthesis. The chemistry demonstrated in this chapter outlines a promising strategy for the formal synthesis of (+)-laurencin.

The first section of this work describes the synthesis of a library of novel rhein analogues that are potential anticancer agents. The design of these compounds takes advantage of the ability for rhein to intercalate into DNA and as the incorporation of an alkylating agent, which serves to covalently modify DNA. In three cell lines, these compounds showed potent cytotoxicity with IC50 in the low to mid-μM range. The second project was focused on the development of an efficient synthesis of 6H-Isoindolo[2,1-α]indol-6-one (24), a core structure for a number of biologically active compounds. The approach is metal-free and uses a Beckmann rearrangement followed by an intramolecular cyclization.

A set of studies centered around the reactions of the active methine compound 1-carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene (the "ring-opened adduct"), obtained by base-induced ring-opening of the Diels-Alder adduct of 5,5-dicyanocyclopentadiene and methyl acrylate, has been carried out. A plan was devised for the anionic (at the dicyanomethyl carbon) ring-opened adduct whereby its reaction with electrophiles, for example Michael reactions with double-bond acceptors, would generate reactive intermediates that would undergo cyclization by tandem conjugate addition to the a,ß,?,d-unsaturated ring p-system to generate bicyclic compounds. In practice, reaction with di-<i>tert</i>-butyl methylidenemalonate, methyl vinyl ketone, and cyclopentenone generated intermediates that exhibited greater tandem reactivity than was anticipated: the bicyclic enolates were found to cyclize further by Thorpe-Ziegler-like reaction with the proximal nitrile to generate, after facile acid hydrolysis, substituted known tricyclic skeleta termed homobrendanes, specifically, tricyclo[5. 2. 1. 0^4,8]decenes. An attempt was made to generalize the reaction to other substrates, among them singly-activated Michael acceptors and 1,2-heteroatom electrophiles, but the generalization of the homobrendane forming reaction did not meet with success. Attempted functional group manipulations to probe the conversion of the homobrendane derived from di-<i>tert</i>-butyl methylidenemalonate to the homobrendane natural product 2-isocyanoallopupukeanane revealed the unreactivity of the skeletal double-bond toward electrophiles and the high reactivity of the ring ketone toward nucleophiles, among them mCPBA which brought about Baeyer-Villiger reaction, and chloride and hydroxide, which brought about addition/elimination reactions to cleave the last-formed homobrendane ring. <br /> The ring-opened adduct was also envisaged as a potential substrate in intramolecular Heck reactions. To this end, Heck substrates were generated from the ring-opened adduct anion and iodo- and bromo-benzyl halides. A key observation at this stage pertained to the unexpected acidity of the ring-opened adduct C5 proton, which could be deprotonated by DBU to bring about allylic isomerization, a finding that would provide a key insight to the pattern of reactivity later evidenced with alkyl propiolates. Optimization of the Heck substrate-generating reaction was followed by Heck reactions under Jeffery's conditions, which generated angular tricycles as intended, accompanied by aromatic compounds generated by base-induced HCN elimination/rearrangement and dehydrogenation. The Jeffery's conditions were optimized to limit the production of aromatics. <br /> The possibility of ring-opened adduct-derived vinyl silane intermediates undergoing cationic cyclizations led to a minor study based upon the bromination of allylsilanes and the elimination of TMSBr from 1,2-dibromo-3-trimethylsilyl compounds, accessible compounds unaccounted for in the review literature. It was determined that the combination of HBr and Br₂ (perhaps as HBr₃) was required to eliminate TMSBr, in contravention of the textbook account of electrophilic substitutions being the inherent reactions of allylsilanes and Br₂. <br /> Unexpected tandem reactivity was observed in the reactions of the anionic ring-opened adduct and alkyl propiolates under catalytic DBU conditions. Rather than tandem cyclization or simple adduct formation, the allenolate intermediates were determined to undergo extremely facile formal allenolate Cope rearrangements involving the ?,d-double-bond of the parent ring. Excess base intercepted the allenolate by deprotonating ring C5 and effecting 1,2-vinyl transfer by 3-<i>exo</i>-trig addition-elimination. The chemistry of the highly delocalized side-chain carbanion in the Cope product was studied in detail.

A set of studies centered around the reactions of the active methine compound 1-carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene (the "ring-opened adduct"), obtained by base-induced ring-opening of the Diels-Alder adduct of 5,5-dicyanocyclopentadiene and methyl acrylate, has been carried out. A plan was devised for the anionic (at the dicyanomethyl carbon) ring-opened adduct whereby its reaction with electrophiles, for example Michael reactions with double-bond acceptors, would generate reactive intermediates that would undergo cyclization by tandem conjugate addition to the a,ß,?,d-unsaturated ring p-system to generate bicyclic compounds. In practice, reaction with di-<i>tert</i>-butyl methylidenemalonate, methyl vinyl ketone, and cyclopentenone generated intermediates that exhibited greater tandem reactivity than was anticipated: the bicyclic enolates were found to cyclize further by Thorpe-Ziegler-like reaction with the proximal nitrile to generate, after facile acid hydrolysis, substituted known tricyclic skeleta termed homobrendanes, specifically, tricyclo[5. 2. 1. 0^4,8]decenes. An attempt was made to generalize the reaction to other substrates, among them singly-activated Michael acceptors and 1,2-heteroatom electrophiles, but the generalization of the homobrendane forming reaction did not meet with success. Attempted functional group manipulations to probe the conversion of the homobrendane derived from di-<i>tert</i>-butyl methylidenemalonate to the homobrendane natural product 2-isocyanoallopupukeanane revealed the unreactivity of the skeletal double-bond toward electrophiles and the high reactivity of the ring ketone toward nucleophiles, among them mCPBA which brought about Baeyer-Villiger reaction, and chloride and hydroxide, which brought about addition/elimination reactions to cleave the last-formed homobrendane ring. <br /> The ring-opened adduct was also envisaged as a potential substrate in intramolecular Heck reactions. To this end, Heck substrates were generated from the ring-opened adduct anion and iodo- and bromo-benzyl halides. A key observation at this stage pertained to the unexpected acidity of the ring-opened adduct C5 proton, which could be deprotonated by DBU to bring about allylic isomerization, a finding that would provide a key insight to the pattern of reactivity later evidenced with alkyl propiolates. Optimization of the Heck substrate-generating reaction was followed by Heck reactions under Jeffery's conditions, which generated angular tricycles as intended, accompanied by aromatic compounds generated by base-induced HCN elimination/rearrangement and dehydrogenation. The Jeffery's conditions were optimized to limit the production of aromatics. <br /> The possibility of ring-opened adduct-derived vinyl silane intermediates undergoing cationic cyclizations led to a minor study based upon the bromination of allylsilanes and the elimination of TMSBr from 1,2-dibromo-3-trimethylsilyl compounds, accessible compounds unaccounted for in the review literature. It was determined that the combination of HBr and Br₂ (perhaps as HBr₃) was required to eliminate TMSBr, in contravention of the textbook account of electrophilic substitutions being the inherent reactions of allylsilanes and Br₂. <br /> Unexpected tandem reactivity was observed in the reactions of the anionic ring-opened adduct and alkyl propiolates under catalytic DBU conditions. Rather than tandem cyclization or simple adduct formation, the allenolate intermediates were determined to undergo extremely facile formal allenolate Cope rearrangements involving the ?,d-double-bond of the parent ring. Excess base intercepted the allenolate by deprotonating ring C5 and effecting 1,2-vinyl transfer by 3-<i>exo</i>-trig addition-elimination. The chemistry of the highly delocalized side-chain carbanion in the Cope product was studied in detail.

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(-) Codeine, (-) morphine, and their semi-synthetic derivatives play an integral role in medicinal analgesia. Due to a complex list of undesirable side effects, their effective use is often complicated and troublesome giving cause for the investigation of novel semi-synthetic analogs for efficacy and side-effect profile. It was envisioned that new and interesting codeine analogs could be synthesized via an opening of a hindered 7,8-[alpha]-epoxide. Classically, hindered epoxides are formed via halohydrin formation and subsequent closure. Interestingly, the 7,8-epoxide formed via bromohydrin closure was resistant to reaction with small nucleophiles, such as oxygen and hydride, but reactive towards large and nucleophilic atoms, such as sulfur and bromide. It was discovered that the epoxide was in fact the less hindered 7,8-[Beta] epoxide via x-ray analysis of various compounds. This hinted at an unexpected rearrangement which most likely occurred during the bromohydrin formation due to the severe steric interactions present in the core structure of codeine. Due to the reversibility of bromonium ion formation, a highly hindered double bond can produce the opposite configuration of what is expected when subjected to aqueous brominating conditions. Many popular alkaloids, including codeine and galanthamine, are biosynthetically formed via a spirocyclic dienone intermediate. In nature these intermediates are formed via an enzymatically driven phenolic oxidation; however in the lab this reaction has proven difficult to reproduce. In a previous Magnus publication, (±) codeine and (-) galanthamine, were synthesized via a common spirocyclic cross-conjugated dienone intermediate similar to the intermediate found in nature. Most importantly, this intermediate was formed without a phenolic oxidation. Instead, a para-alkylation of an appropriately substituted phenol efficiently created the key intermediate. Expanding on this phenolic alkylation strategy, various biaryl systems were built in order to investigate the scope and limitations of this reaction. Multiple para- alkylations proved successful while ortho- alkylations unveiled an interesting rearrangement which occurs during the reaction. Lastly, it was determined that a 7-membered ring could not be set using a phenolic alkylation strategy. / text

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