A novel manifold has been developed, catalytic in phosphorus (V), that promotes the dehydration reaction of an alcohol to give the symmetrical ether product. This has been achieved through the development of a novel dioxyphosphorane catalyst that, in conjunction with a triflic acid cocatalyst, conducts the coupling reaction without the need for any additional stoichiometric reagents. This has allowed the omission of the explosive diazo-compounds that are required in the widely-accepted Mitsunobu conditions, and has reduced the amount of inconvenient and difficult-to-remove phosphorus waste that is usually associated with phosphorus-mediated reactions. This work constitutes the first example of a phosphorus (V)-catalysed Mitsunobu-type etherification reaction.

This thesis details the development of methods for and application of the synthesis of carbon carbon bonds using organic sulfur(IV) chemistry. More specifically, the formation of C(sp2) C(sp3) and C(sp3) C(sp3) bonds is explored in detail. The necessity for this research stems from a correlation between a high proportion of sp3 centres in drug candidates, and their success in clinical trials. By facilitating the synthesis of drug candidates with higher fractions of sp3 hybridised carbon atoms, it is hoped that the rate of candidates proceeding through clinical trials may increase. The first topic addressed is the ligand coupling reactions of sulfoxides. In such reactions, the treatment of appropriately substituted sulfoxides with organometallic reagents forms C(sp2) C(sp3) coupling products via σ sulfurane intermediates. These reactions have the ability to excel where transition metal catalysed cross couplings fail; in the coupling of electron deficient (hetero)aromatic groups and alkyl groups. Very few reports have been published detailing the scope and utility of this reaction. The application of this methodology to the synthesis of diarylmethanes is explored in detail. Diarylmethanes are designated as privileged structures for the presence of these moieties in a vast array of diversely functional drug products. Investigation of the scope of the ligand coupling reaction allows for the elucidation of (hetero)aromatic moieties which can undergo this reaction. The depth of analysis in which the scope of benzylic substituents is studied allowed for the elucidation of previously unreported trends, which have been assigned to steric and electronic characteristics of the σ sulfurane intermediates. This knowledge gained is applied to the synthesis of both enantiomerically enriched diarylmethanes and well known drug products. Further exploration of the scope of ligand coupling reactions focusses on the coupling of α functionalised alkyl groups. Remarkable success is found in this completely unexplored area. Benzylic ethers, carbamates and halides are synthesised through a combination of inter molecular and intra molecular ligand coupling reactions. It is proposed that these reactions would be suitable for use in the synthesis of natural products to prove their utility. A newly-discovered sulfoxide homologation is detailed, which occurs upon reaction of sulfenate by products with the aforementioned benzylic halides, both synthesised by a ligand coupling reaction. This is particularly interesting since a similar homologated sulfoxide is found in the substructure of omeprazole, a blockbuster proton pump inhibitor. The second topic addressed is the synthesis of (±)-TAN1251A. The envisaged route proceeds through a novel palladium catalysed [3+2] cycloaddition of sulfinimines, forming methylene pyrrolidines. Previous work focussed on the use of this methodology to produce a diamine, mono-protected as a sulfonamide. A key aspect of the research presented in this thesis is the formation of the C ring of the spiro fused 1,4 diazabicyclo[3.2.1]octane moiety. Initial investigations focus on the synthesis of a pyruvic acid fragment to react with the aforementioned diamine. This concept is developed into the use of pyruvic acid synthetic equivalents: azlactones. A late stage intermediate is produced, however formation of the C ring from this intermediate is not observed. Synthesis is hampered by the deprotection of the sulfonamide, which forms several by-products under the strongly acidic conditions required. A revised retrosynthesis proposes that early deprotection of the diamine sulfonamide would prevent complications. The use of a simplified fragment to facilitate C ring formation is devised, comprising of an α-haloketone. Synthesis of the unprotected diamine is accelerated by serendipity, where a reductive amination also effects the elimination of a sulfinyl group. Formation of an α haloketone fragment is found to be troublesome, however synthesis via the natural product chavicol provides the required functionality. A wide variety of conditions are examined to effect the combination of these fragments. While coupling of the fragments is successful in providing another late-stage intermediate of (±) TAN1251A, formation of the desired C ring is not achieved. Finally, the potential to effect an enantioselective synthesis of (±)-TAN1251A is confirmed using a chiral sulfinamide to direct diastereoselective ketone reduction.

This thesis details the use of chiral diamine derived catalysts in asymmetric addition reactions. Three separate projects are outlined within. The first project involved the investigation of dibenz[c,e]azepinium salt 113 as a catalyst for the aldol reaction. The catalyst was synthesised in 4 steps from commercially available 1R,2R-diaminocyclohexane in 74% overall yield. It was found to be an efficient catalyst in the aldol reaction of cyclic ketones with a range of aromatic aldehydes, giving high yields, diastereo- and enantioselectivities. This catalyst was also found to be effective when acyclic ketones were used, in which case the major diastereoisomer produced was no longer an anti-aldol but a the syn-aldol. A catalytic cycle for these reactions is proposed, with the stereochemical outcome of these reactions being further investigated by computational calculations. The second project investigated the use of chiral primary amine catalysts in the conjugate addition of N-heterocycles to α,β-unsaturated ketones. It was found that commercially available 1R,2R-diaminocyclohexane 114 was an efficient and enantioselective catalyst for the addition of pyrazoles to α,β-unsaturated ketones. Through comparison with the performance of related catalyst structures we propose a catalytic cycle in which 114 forms bonds with both the α,β-unsaturated ketone and the incoming pyrazole. Alternative chiral amines derived from camphor sulfonic acid were investigated as catalysts for the conjugate addition reaction; these proved to be relatively poor catalysts giving the product with a low enantiomeric excess. Finally, an investigation into intramolecular N-conjugate additions was performed. We found that 9-epi-9-amino-9-deoxyquinine derived squaramide 355 was a highly enantioselective catalyst for the intramolecular cyclisation of sulfonamides to α,β-unsaturated ketones. Best results were seen with α,β-unsaturated ketones conjugated to an aryl group, however squaramide 355 also proved to be an enantioselective catalyst for the cyclisation of methyl ketone and ester conjugated alkenes. In the latter two cases higher temperatures and catalyst loadings were required. In conjunction with molecular modelling studies we propose a catalytic cycle that accounts for the observed stereochemistry.

Eight-membered rings are notoriously difficult to synthesise due to unfavourable transannular and conformational strain within the ring system. That being said, there are many biologically active natural products that contain such ring systems. For instance, potent anti-cancer compound Taxol®, has an eight-membered ring at its core. Many contemporary synthetic routes to 8-membered rings require the use of complex cyclisation precursors, due to the difficulties associated with the formation of 8-membered rings. The synthesis of such precursors commonly include multiple steps, with each step consuming researcher time, effort and resources. Described herein is new methodology that can be used to synthesise eight-membered carbocyclic cores, in a one-pot, single step synthesis from easily attainable starting materials. A novel Cannizzaro triggered cascade allowed swift formation of eight-membered rings from three components without the need to synthesise, purify and characterise unwanted intermediates. The key step in the cascade is a Cannizzaro-like 1,5-hydride transfer that simultaneously forms a carbanion and powerfully Michael accepting ynone. Annulation is achieved through the reaction of these centres. Application of this methodology led to the synthesis of 30 novel ortho-fused eight-membered carbocycles, in up to 81% yield. Utilisation of a ‘temperature switch’, based on competition of kinetic and thermodynamic pathways, enabled the synthesis of 7 novel 1,2-dihydronaphthalen-1-ol or naphthalene cores. The mechanisms of the aforementioned transformations have also been probed both experimentally and computationally to support our proposed mechanism. With the aim of synthesising a diverse library of 8-membered ring derivatives, the Cannizzaro cascade was extended to enable trapping of a reactive intermediate with electrophiles. A Diversity Oriented Synthetic project was undertaken using the products of the 3- and 4-component cascade reaction as starting points to build molecular diversity. In a maximum of three-steps, from commercial bromo-aldehydes, we have been able to develop a library of compounds that contain; four-, five-, six-, eight- and nine-membered ring systems; nitrogen, sulfur and oxygen containing heteroaromatics; bicyclic and tricyclic fused-ring systems; and functional groups including a carboxylic acid, amides, lactams, alcohols, ketones, halogens, nitriles, esters, oximes, alkenes, alkynes, enones and a pyrazalone ring. Representative examples from this library have been through a limited number of biological screening assays and have shown biological activity in two different areas. It was found that some compounds in this library are able to stimulate the secretion of Glucagon-like Peptide-1, a possible target for the treatment of type II diabetes. Thesis for Reader Access does not include full text of published articles included into As Examined Thesis.

Chapter 1.Copper-Catalysed Borylative Coupling of Vinylazaarenes and N-Boc Imines. Methodology for the copper-catalysed three-component couplings of vinylazaarenes, bis(pinacolato)diboron, and N-Boc imines has been developed. Oxidation of the initially formed boron species gives azaarene-containing, Boc-protected amino alcohols with reasonable to good diastereoselectivities. Additionally the synthetic utility of the reaction products have been demonstrated. The crude boron species have been shown to undergo a Suzuki-Miyaura cross coupling to give further functionalised products. Finally, facile deprotection of the reaction products is possible. Chapter 2. Chain Walking of Allylrhodium Species in Rhodium-Catalysed Nucleophilic Allylations of Imines and Aldehydes. Allylrhodium species derived from δ-trifluoroboryl β,γ-unsaturated esters undergo chain walking towards the ester moiety. The resulting allylrhodium species react with imines to give products containing two new stereocenters and a Z-alkene. By using a chiral diene ligand, products can be obtained with high enantioselectivities. A pronounced matched/mismatched effect with the chirality of the allyltrifluoroborate is also observed. In an analogous reaction a rhodium-hydride species has been shown to catalyse the addition of diene esters and aldehydes via allylrhodium intermediates which also undergo chain walking towards the ester moiety. The methodology enables allylation of aromatic aldehydes with compounds containing both diene and ester functionalities linked by carbon chains of up to eight carbons in length.

High pressure X-ray crystallography is an effective tool for studying the behaviour of systems in the solid state. It is becoming an increasingly popular technique and offers a way to determine and monitor the behaviour of systems, which in some cases is necessary in order for those particular materials to be used in real-world applications. This thesis explores the use of high pressure X-ray crystallography to understand the behaviour of systems such as metal-organic frameworks (Chapters 4and 5) and the coordination complexes, [1,4-C6H4{PPh2(AuCl)}2](Chapter 6) and chloro(4-ethoxycarbonyl-6-phenyl-2,2′-bipyridyl)platinum (Chapter 7). It also describes hydrostatic limit determinations carried out on 4:1 MeOH/EtOH with additional additives such as silicon grease and/or crystals of [PdCl2([9]aneS2O)] to see how the hydrostatic limit might be manipulated by the use of these additives. It has been possible to determine the hydrostatic limit of a possible pressure-transmitting medium, namely RS3000, which showed an increased pressure limit when compared to the hydrostatic limits for other similar media. This thesis therefore covers a wide range of studieshighlighting some of the diversity that this fieldoffers. To betterunderstand the behaviour of the systems studied, several ancillary techniques have been employed including Hirshfeld surface analysis, Raman spectroscopy, UV/visible spectroscopy and theoretical calculations. In all cases these techniques provided useful information which complemented the results of the high pressure X-ray crystallographic studies.

Enantioselective Nickel-catalysed anti-Carbometallative Cyclisations of Alkynyl Electrophiles Enabled by Reversible Alkenylnickel E/Z Isomerisation. Highly enantioselective anti-carbometallations of alkynes bearing tethered ketones is described using a Ni(II) salt and a commercially available chiral phosphinooxazoline ligand. Due to the syn-selective nature of alkyne-migratory insertion, many examples of carbometallative processes giving the cyclised syn-products have been reported, however, anti¬-carbometallative processes are rare. The mechanism of this anti-carbometallation is thought to occur via an alkenylnickel E/Z-isomerisation of the organometallic species formed after initial alkyne migratory insertion. Although a number of examples of such isomerisaions have been reported, the utilisation of the phenomina in ring-forming reactions to give anti-carbometallation products is much less well explored. Further reaction development for the nickel-catalysed anti-carbometallative cyclisations of alkynyl electrophiles has allowed for the synthesis of enantioenriched cyclopentenones using malonates as electrophiles. The use of the trifloroethanol leaving group on a malonate electrophile is important for efficient reactivity and allows the previously unreactive ester electrophile to be used. However, inorder to obtain high enantioselectivities and aryl group at the quaternaty centre of the substrate is required.

This thesis describes the utilisation of a new, facile route for rapid ligand synthesis for the design, synthesis and characterisation of metal-organic frameworks (MOFs), and the subsequent refinement of ligand synthesis to discover a 2-step green alternative synthetic route to an analogous ligand for use in the same. From these ligands, two series of MOFs are detailed; a Cu(II) series with simulated isotherms showing promising CH4 and CO2 high pressure uptake, and two Zr(IV) MOFs with enhanced stability and their measured high pressure isotherms. Chapter 1 introduces the need for highly functional materials to answer the needs of current energy production crises; with the production of CO2 from fossil fuels predicted to continue dangerously damaging the environment for decades to come, while the fossil fuel energy sources themselves run out, alternatives are clearly needed to continue powering society. MOFs are introduced as potential materials which can fulfil both of these needs. Chapter 2 describes the synthesis of the H4LX series, which utilise the Suzuki-Miyaura cross-coupling reaction to generate a large quantity of a versatile ligand pre-cursor (3,5-di(p-carbethoxy)benzene boronic acid), which is then used to generate a large number of ligands via a further Suzuki-Miyaura cross-coupling reaction with a dihalogenated core. A green synthetic route to an analogous ligand to the first in the series (H4L1P, which differs from H4L1 by the replacement of two phenyl rings with pyridyls) is then described, which reduces the synthetic steps by 66% (2 steps instead of 6), and the cost by 95% (£0.51/g instead of £11.68/g). Chapter 3 describes the design, synthesis, and characterisation of a series of Cu(II) metal-organic frameworks (MFM-191 to 198), and their respective simulated isotherms, which enable rapid identification of promising frameworks for materials which theoretically approach and even exceed the American Department of Energy’s (DoE’s) target value for CH4 working capacity, and also potentially provide an alternative to current proposals for CO2 storage and shipping. The discussion on these frameworks is split into two studies: Exploration of the effects of interpenetration and classes thereof on low and high pressure gas sorption (MFM-191,192 and 193), and analysis of attempts to fine tune the high pressure uptake of a series of non-interpenetrated isoreticular structures via extension and functionalisation of the central core of the ligand (MFM-193 to 198). The first group of frameworks demonstrates how interpenetration aids low pressure uptake, but hinders maximum high pressure uptake. MFM-191 (which exhibits 2-fold interpenetration, class IIa) displays an uptake of CH4 of 1.97 wt% at 1 bar and 21.40 wt% and 80 bar, 298 K and an uptake of CO2 of 2.88 mmol/g at 1 bar, and 16.69 mmol/g at 30 bar, 298 K; while MFM-193 (a non-interpenetrated MOF with the same topology) demonstrates a greater difference between uptakes, with uptakes for CH4 of 0.85 wt% at 1 bar and 47.06 wt% for 80 bar, 298 K, and uptakes for CO2 of 0.65 mmol/g at 1 bar and 40.82 mmol/g at 30 bar, 298 K. This larger difference is due to the decreased host-guest interactions at low loadings, and works in favour of a better working capacity for CH4 for the non-interpenetrated framework. Alteration of the class of interpenetration (from class IIa to class Ia) results in overall uptake behaviour which lies between the two, displaying an uptake for MFM-192 of CH4 of 2.11 at 1 bar, and 31.36 wt% at 80 bar, 298 K and an uptake of 2.89 2.89 mmol/g at 1 bar and 24.07 mmol/g at 30 bar for CO2 at 298 K. The non-interpenetrated series of MOFs (MFM-193 to 198), shows how upon functionalisation of the central core of ligand H4L1, the gas sorption properties are increases in accordance to the aromaticity of the ligand, with an increase in maximum volumetric uptake (at 80 bar, 298 K) of CH4 from 233.29 to 251.89 cm3/cm3 from MFM-193 (with H4L1, a ligand with a phenyl ring as the central core) to MFM-195 (synthesised from H4LAN, a ligand with an anthracene moiety as its central core). Surprisingly, the amine-functionalised MOF (MFM-196) displays the lowest uptake of both CH4 and CO2 at high pressure compared to the other functionalised MOFs (MFM-194 and MFM-195) Extension of the ligand core from one phenyl ring to biphenyl and pyrene based ligands affords MFM-197 and MFM-198, which in turn display the highest theoretical gravimetric CH4 working capacities 5-80 bar (48.51 wt% and 44.15 wt% at 298 K, respectively). Furthermore, working capacities calculated from the 273 K simulated isotherms for MFM-198 (the pyrene functionalised framework) show that this MOF is capable of exceeding the DoE target for gravimetric working capacity of 50 wt% (and nearing the volumetric target of 264 cm3 cm-3), by delivering 52.3 wt% and 256.9 cm3 cm-3 between 5-80 bar. However, upon attempts to activate these Cu(II) frameworks, none were stable enough to obtain a permanent porosity, even from ‘soft’ activation methods such as supercritical CO2; therefore, new frameworks were sought which would be designed to have enhanced stability. Chapter 4 describes the synthesis of two Zr(IV) MOFs, synthesised from H4L1 and H4L1P (MFM-421 and MFM-422) designed to display enhanced stability over the Cu(II) MOF series, and allow acquisition of experimentally gathered high pressure data. This is particularly interesting for the MOF synthesised from H4L1P, as the green, cost-effective synthesis conditions of the ligand are potentially valuable for industrial applications. Both MOFs display an increase in stability over the Cu(II) series, with a measureable BET of 3,300 m2/g for MFM-421 and 2,500 m2/g for MFM-422. The high pressure CH4 and CO2 capacities of both frameworks were measured, and, while they were lower than the simulated Cu(II) series, they were highly competitive compared to published MOFs. MFM-421 is shown to have the fourth highest CH4 gravimetric working capacity at 298 K (compared to a list of the highest experimentally recorded MOFs for methane working capacity), and MFM-422 the sixth, measuring values of 25.7 wt% and 22.8 wt%, compared to the three highest of 31.0 wt%, 35.0 wt% and 42.3 wt% for MOF-177, MOF-205 and Al-soc-MOF-1, respectively. Importantly, compared to HKUST-1 (the only framework amongst this list that is cheaper than H4L1P to buy/synthesise), both of these frameworks exhibit higher gravimetric working capacities (which for HKUST-1 is 16.3 wt% at 298 K). The analysis of CO2 high pressure isotherms for potential in storage and shipping shows that these MOFs exhibit an increase in storage capacity at 298 K, 30 bar over capacity of a tank at the same conditions of over 500% for MFM-421 (7,708 mol/m3 compared to 1,458 mol/m3) and over 650% for MFM-422 (9,605 mol/m3). While the highest of these values still stands at only 43% of the value of a tank at 26.5 bar and 263 K, the ability to store this much CO2 at ambient temperatures allows more flexibility in route and less energy intensive storage conditions. Chapter 5 summarises the CH4 and CO2 storage properties of these structures and draws overall conclusions from the work.

This thesis describes the design and synthesis of a series of Cu(II)-paddlewheel based metal organic frameworks (MOFs) for the adsorption of gaseous fuels and pollutants. The frameworks comprise V-shaped pyridyl carboxylate ligands, which are progressively modified to increase gas adsorption capacity and selectivity of the resultant materials. Chapter 1 introduces the history and structure of MOFs, including an exploration of their varied applications. Particular attention is paid to gas adsorption within these materials, considering the best performing materials for each gas discussed. Chapter 2 explores the ability of uncoordinated pyridyl groups to form strong interactions with adsorbed CO2. A new self-interpenetrated Cu(II) MOF (MFM-170) is synthesised from a V-shaped pyridyl carboxylate ligand, in which the pyridyl nitrogen coordinates to the axial site of the interpenetrating net. The porosity and gas adsorption properties of this material are discussed in detail. Chapter 3 describes how functional groups can introduce binding sites into MOFs, strengthening framework-adsorbate interactions and improving gas adsorption capacities. Three isostructural analogues of MFM-170 are synthesised (MFM-171, MFM-172, MFM-173), each with a different functional group directed into the pore. Differences in the gas adsorption properties of these materials are rationalised by identification of CO2 binding sites by IR microspectroscopy and Single Crystal X-ray Diffraction experiments. Chapter 4 draws on knowledge of CO2 binding sites identified in Chapter 3 to selectively target areas of the framework where strongly coordinating functional groups would have the greatest effect of CO2 adsorption and selectivity. A new Cu(II) framework (MFM-175) is reported, incorporating triazole groups directed into the void. The structure, stability and gas adsorption properties of MFM-175 are studied in detail and compared to MFM-170. Chapter 5 investigates the synthesis of a non-interpenetrated analogue of MFM-170 with the aim of liberating the pyridyl nitrogen group to improve framework-adsorbate interactions. A new Cu(II) MOF (MFM-176) is synthesised, featuring a two-fold interpenetrated structure. Nevertheless MFM-176 demonstrates improved selectivity parameters and additionally a promising strategy for the successful synthesis of a non-interpenetrated framework.

The synthesis and application of aldimines has been well documented in the last twenty years since Ellman’s publication of the synthesis of optically pure tert-butyl sulfinamide. Within the Stockman group their application to the aza-Darzens reaction has been explored. This work is an expansion of the previously reported aza-Darzens synthesis of aziridine 2-carboxylates with particular emphasis on increasing the scope and specific attention on heteroaryl-substituted aldimines and ketimines. A wide range of sulfinimines was screened with a variety of ester partners giving di- and tri-substituted aziridine 2-carboxylates. Overall the yields were good with di-substituted aziridines giving the best results. Tri-substituted aziridines were produced in variable yields and selectivity with some heteroaromatic substrates tolerated. Attempts to synthesise vinyl aziridine 2-carboxylates proved to be disappointing with a cyclopropane byproduct being observed. Attempts to avoid production of the byproduct were unsuccessful. It has been shown that vinyl aziridine 2-carboxylates will undergo rearrangement to cyclic sulfoximines. Mechanistic studies have indicated that this proceeds through a concerted sigmatropic rearrangement as neither radical traps nor polar solvents inhibited the reaction. The synthetic utility of aldimines as chiral precursors to isothiazolidines was briefly investigated, however this ultimately proved unsuccessful.