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The concept of lead-oriented synthesis (LOS) seeks to address to the paucity of diverse compounds with appropriate properties for biological screening. This thesis focuses on the preparation of diverse scaffolds, which, following decoration, may provide access to lead-like compounds. Key polyfunctionalised building blocks were prepared to enable the synthesis of such scaffolds by applying small tool-kits of robust synthetic methodologies. Computational tools were used to guide the development of key methodologies and to target the preparation of specific scaffolds. In addition, computational tools were used to retrospectively analyse the ability of the scaffolds prepared to provide access to lead-like space. Chapter 1 discusses ideal molecular properties for drugs and leads, modern synthetic approaches to the preparation of diverse screening compounds, and the emergence of LOS as a concept to resolve the challenge of sourcing large numbers of ideal screening compounds. Chapter 2 details the preparation of small polyfunctionalised building blocks through the allylation of amino acid-derivatives. A building-up (‘bottom-up’) approach was used to prepare scaffolds, exploiting the intramolecular capture of pendant nucleophiles at alkene or ester functionalities, and the use of transition metal-catalysed cyclisations. Four building blocks were used to prepare 22 scaffolds. A virtual library of 1110 compounds was enumerated from the scaffolds, of which 66% were found to be lead-like. Chapter 3 describes the preparation of larger polycycles using an intramolecular [5+2] oxidopyrylium cycloaddition. The two polycyclic assemblies prepared were deconstructed using a ‘top-down’ approach to give six scaffolds. A virtual library of 798 compounds was enumerated from the scaffolds, of which 72% would be lead-like. Chapter 4 compares the value of the different LOS approaches developed, this considers the ability of the scaffolds to provide access to lead-like space, their three-dimensionality, and the synthetic economy of their preparation.

It is a common misconception that the colony at Botany Bay was founded purely so that Britain could rid herself of her convicts. This would have made the alleged convict crisis in Britain a first order consideration for the Pitt Government. It was not. Pitt had two major problems on coming to office - finance and trade - and the solutions to them were not mutually exclusive. Each depended on his skill at filling Treasury coffers and on the successful completion of the complicated trade treaties with France, Holland and Spain after the American War of Independence. Numerically speaking there was no convict crisis, rather a prison problem. The towns and cities in England and Wales refused to build the expensive prisons required under legislation passed in 1778-9; instead seeking a resumption of transportation. Pressure was brought on Government by the merchants in the House of Commons. They dominated the Beauchamp Committee of 1785, which recommended a resumption of that punishment. Pitt saw the advantages to be gained from having an armed settlement in the Far East. During his commercial treaty negotiations in 1786-7 he did not wish to arouse the suspicion of his European rivals, but still saw the opportunity a colony would present in case there was a resumption of hostilities. New South Wales helped solve a number of Pitt's problems. Most importantly, the swing to the east helped him financially. Next it secured the southern trade route to China and placed a strategic base at the rear of the French, Dutch and Spanish possessions. And, as a matter of relatively minor detail, it also salved the conscience of the Enlightenment lobby by solving his prison problem. Unfortunately a generation of war intervened shortly after the settlement was founded and not until 1815 did it start to achieve what Pitt originally envisaged.

The Bovine Igneous Complex (BIC), located 8 kilometers southeast of the town of L’anse, Michigan, is a small basin-shaped mafic/ultramafic intrusion emplaced in the southwestern part of the Paleoproterozoic Baraga Basin. Although age dating of the BIC intrusion has so far been unsuccessful, the intrusion was very likely emplaced during the early magmatic stage of Midcontinent Rift development, given its similarities to other mineralized early stage intrusions, such as Tamarack and Eagle. Targeted by Kennecott as a Cu-Ni-PGE prospect, the intrusion has undergone extensive exploration drilling since 1995. To date, the intrusion has been found to be only weakly to moderately mineralized with Cu-Ni-PGE sulfides. Metal tenors provided by initial drilling averaged less than .5% Cu and Ni, and less than 350 ppb Pt and Pd (Rossell, 2008). Preliminary evaluation of field mapping, core logging and geochemical data by Rossell (2008) interpreted the intrusion to be a layered ultramafic/mafic body with an igneous stratigraphy composed of a basal wehrlite, overlain by a clinopyroxenite, and capped by a gabbro. This study was undertaken to further refine the igneous stratigraphy of the BIC, specifically its phase layering and cryptic variation, toward the goal of better understanding its emplacement, crystallization, and mineralization history. For this study, two drill cores (BIC01-01 and 08BIC-044) that profile the BIC were investigated for their petrographic attributes, cryptic mineral compositions, and whole rock lithochemistry. In addition, a detailed (1:6,000) re-mapping of the BIC was conducted. This study has found that the lithostratigraphy of the main intrusion is generally similar to that found by Rossell (2008), but when mineral modes and textures are factored in, the cumulate stratigraphy of the BIC is found to progresses from an olivine cumulate with intercumulus augite and plagioclase (feldspathic wehrlite unit), to an augite+olivine cumulate with intercumulus plagioclase (feldspathic olivine clinopyroxenite unit), to an augite+oxide±olivine cumulate with intercumulus plagioclase (oxide clinopyroxenite unit), and finally, a plagioclase+augite+oxide cumulate (oxide gabbro unit) at the top. Complimenting this cumulate phase layering is a smooth cryptic variation of upward decreasing mg# in olivine and augite composition. While this cumulate stratigraphy of Ol #1; Ol + Aug #1; Ol + Aug + Ox #1; Aug + Pl + Ox – Ol #1; Aug + Pl + Ox is evident in the field exposures and in the BIC01-01 drill core, a lower ultramafic zone was discovered in the longer 08BIC-044 core. This lower ultramafic zone is composed of feldspathic wehrlite unit (Ocp cumulate) and overlying feldspathic olivine clinopyroxenite unit (COp cumulate). Although generally similar to the same units composing the lower part of the main intrusion (called the upper ultramafic zone), there are subtle differences in mode, texture and composition that indicate that the lower ultramafic zone is a separate intrusive component of the BIC. The emplacement model is proposes that the system begins with the injection of a small pulse of magma through the Archean gneisses and into the base of the Michigamme Formation. This small pulse fractionally crystallizes from the base up, a feldspathic wehrlite followed by a feldspathic olivine clinopyroxenite. The conduit is then reopened and a second larger magma pulse is intruded above the first pulse and fractionally crystallizes producing the cumulate stratigraphy seen in outcrop and drill core BIC01-01. Due to the collinear nature of trace element and rare earth geochemistry from the lower ultramafic, upper ultramafic, and gabbro zones it is concluded that the two magma pulses came from the same parent magma source. This parent magma was determined to be a high magnesium low aluminum tholeiitic basalt with an Mg# between 68 and 70. These estimates were derived by the manipulation of geochemistry obtained from a sample located in the basal chill. Chalcophile element geochemistry suggests the BIC underwent three episodes of sulfur saturation. The first event occurred as the initial pulse, which formed the lower ultramafic zone, was injected into the surrounding country rock. Next, as the second pulse of magma injected above the first, the magma became oversaturated leading to a spike in metal tenors at the base of the upper ultramafic zone. The BIC reached sulfide saturation for a third time in passive event caused by progressive fractional crystallization.