The total synthesis of citrafungin A (i),1 the determination of the absolute stereochemistry2 of CJ-13,981 (ii) and CJ-13,982 (iii) and the formal total synthesis of (–)-trachyspic acid, by making lactone iv,3 were achieved from a common intermediate (v). [Diagram omitted] Dioxolanone v was prepared on a multigram scale starting from commercially available 4-benzyloxy-butyric acid using, as key steps, an enantioselective syn-aldol reaction of a chiral oxazolidinone and a diastereoselective Seebach alkylation of a 1,3-dioxolan-2-one derivative. [Diagram omitted] From dioxolanone v, citrafungin A (i) was synthesised in 13 steps, CJ-13,981 (ii) and CJ- 13,982 (iii) in 9 steps and the intermediate lactone (iv) for the formal synthesis of (–)-trachyspic acid in 5 steps. Based on our recent advances on resorcylates metabolites,4 we carried out the total synthesis of aigialomycin D (vi),5 a potent 14-membered resorcylic macrolide, without the need for phenol protection, using the C-acylation of a keto-dioxinone dianion (or monoanion), a cascade sequence consisting of ketene generation, alcohol (vii) trapping and aromatization, and ring closing metathesis. [Diagram omitted] References: (1) Calo, F.; Richardson, J.; Barrett, A. G. M. J. Org. Chem. 2008, 73, 9292. (2) Calo, F.; Bondke. A.; Richardson, J.; White, A. J. P.; Barrett, A. G. M. Tetrahedron Lett. 2009, 50, 3388. (3) Calo, F.; Richardson, J.; White, A. J. P.; Barrett, A. G. M. Tetrahedron Lett. 2009, 50, 1566. (4) Navarro, I.; Basset, J.-F.; Hebbe, S.; Major, S.; Barrett, A. G. M. J. Am. Chem. Soc. 2008, 130, 10293. (5) Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett. 2009, 11, 4910-

Nuclear receptors (NRs) are a large family of mammalian transcription factors that have the particularity of binding directly to DNA and regulating the expression of adjacent genes. Liver receptor homologue-1 (LRH-1) is a NR from the subfamily 5 (steroidogenic factor-like) and plays a prominent role in development, reverse cholesterol transport, bile-acid homeostasis and steroidogenesis, as well as being implicated in the control of aromatase expression. In addition, Ali et al. showed that LRH-1 acts as a key regulator of the estrogen response in breast cancer cells through the regulation of estrogen receptor-α (ERα) expression. As a crystal structure of LRH-1 was available, the design of new potential LRH-1 antagonists was based on a computer-aided drug design (CADD) approach. It was believed that virtual agonist and antagonist analogues would bind at the same site within the core of the ligand-binding domain (LBD) but demonstrate different binding modes. Binding of an antagonist would induce a conformational change within the LBD of LRH-1, involving a rotation of helix 12 (H12) by direct steric clashes between this helix and the ligand and as a consequence, prevent co-activator recruitment. The LRH-1 LBD was identified as mainly hydrophobic and as one of the largest in the NR family. Three series of analogues have been designed. Steroid-based compounds bearing a challenging C-2 ether linkage were initially synthesized followed by analogues structurally related to anti-estrogen agents tamoxifen and raloxifene (Scheme 0). [diagram included in print copy, unable to reproduce electronically] Scheme 0 – Three series of virtual LRH-1 antagonists from our CADD approach [diagram label]

This thesis is divided into three chapters. In the first, the methods currently available for the synthesis ofphenols from acyclic precursors are reviewed. The review concentrates on methods that have been usedto form a range of phenols and is divided up according to the type of chemistry employed. The secondchapter describes the development of a novel route to phenols. Initial optimisation results are describedfirst, followed by the synthesis of a library of phenols. The majority of these have not been reportedpreviously. The attempted extension of this work to the formation of anilines, nitrobenzenes and morehighly oxygenated aromatics is also presented. Finally, work towards the synthesis of the aglycone ofpseudopterosin A is described, following a route that would utilise the phenol-forming chemistry in amore complex natural product environment. The final section details the experimental procedures usedto form the compounds described in section two, along with associated spectroscopic data.

The research described in this thesis covers two fields of investigation: 1) Biaryl and styrene Synthesis by Cross-Coupling of Fluorous-tagged Photo-activated Arylgermanes and Towards the Preparation of Boscalid and Analogues Biaryls are generally prepared by cross-coupling between aryl metals. However, even the most robust of these aryl metal species cannot be carried through complex synthetic sequences due to their reactivity particularly towards electrophiles. In this thesis, the development of trialkylgermanes as ‘safety-catch’ coupling precursors for biaryl and styrene synthesis was achieved. The safety-catch germanes are fluorous-tagged to facilitate parallel synthesis using fluorous SPE techniques and are activated towards Pd(0)-catalysed cross-coupling with aryl bromides by oxidative photolysis using a UV lamp. The stability profile of the fluorous-tagged arylgermanes was examined. They are stable under strong basic, nucleophilic and reductive conditions but labile in acidic and oxidative environments. This stability profile provides unique opportunities for synthetic route design in target orientated syntheses by allowing the germane group to be installed early in the sequence but only activated for cross-coupling when required. This method has been applied to the synthesis of the plant anti-fungal agent boscalid® and its alkynyl derivatives. 2) Novel Protocol for Solid Phase Synthesis of Radio-iodinated Ligands for Imaging of Cannabinoid Receptors in the Brain Rimonabant® is a CB1 receptor antagonist indicated for the treatment of obesity, metabolic syndrome, addiction and smoking cessation. Radio-labelled analogues are potential PET (Positron Emission Tomography) and SPECT (Single Photon Emission Computed Tomography) imaging agents for visualising the distribution of cannabinoid receptors in the brain for medical research. Conventional methods for the preparation of radio-iodinated cannabinoid receptor ligands employ organostannane precursors which undergo electrophilic ipso-iododestannylation with concomitant formation of toxic organostannane by-products. Rigorous removed of organostannane residues is necessary prior to injection the ligand for in vivo experiments. In this thesis, a novel, non-toxic, solid-supported and facile approach for the parallel synthesis of iodinated cannabinoid receptor ligands based on the skeleton of rimonabant has been demonstrated.

The Pd-catalyzed amination of aryl halides (Buchwald-Hartwig amination) has become a versatile and widely used technology to synthesize and produce aromatic amines relevant in pharmaceutical and agrochemical industries. The aim of the work presented in this thesis is to achieve a better mechanistic understanding of this reaction. The methodologies used were not traditional and focused on kinetic studies, carried out using in-situ tools, mainly reaction calorimetry. Reactions using different amines have been considered: the kinetic behaviour of a straight-chain primary amine (n-hexylamine) was found to be very different from the kinetics of benzophenone hydrazone. This difference was rationalised by considering the mechanism and by proposing a change in the rate-limiting step. Spectroscopic studies, aimed at determining the catalyst resting state, supported our proposals. We subsequently started studies on the competitive system of two amines and one aryl halide. We found that, surprisingly, the less reactive amine, when in competition, reacted first. This intriguing behaviour was rationalised by considering the Curtin- Hammett principle and by recognizing that in this case selectivity was controlled by relative stability of intermediates, not relative reactivity. This was termed “monopolizing” regime, in contrast to the “major-minor” regime in which the minor but more reactive intermediate produces the major product. Subsequent studies revealed that the benzophenone hydrazone product also binds to the Pd/BINAP catalyst, and, during the hexylamine reaction, inhibits the rate and induces a change in the rate limiting step and catalyst resting state. Reactions using benzophenone imine were then studied. The competitive system of benzophenone imine and benzophenone hydrazone provided an example of a system showing a change from the “monopolizing regime” to the “major-minor” regime. These concepts can be generalized and applied to explain selectivity in other competitive catalytic systems.

The reaction of imidoyl chlorides IMC1-9 with lithium β-diketiminates Li(BDKx) (x = iPr, iPr2, tBu, Me3, iPr2/OMe) yields β-triketimines L1-16 which represent a new class of facially-coordinating neutral tridentate nitrogen ligands. The synthetic route is highly modular, allowing for wide variation of substitution patterns and thus fine control over the steric demands of the ligands. In all but two examples (L11 and L12) the β-triketimines exist in solution either solely as their enamine-diimine tautomers, or as equilibrium mixtures of the two. The processes of solution-phase equilibration have been studied by NMR spectroscopy. The molecular structures of L1, L10 and L11 are presented, and for each case a single differing tautomer or isomer is observed exclusively. The majority of the ligands yield fac-(L)M(CO)3 adducts upon reaction with group 6 metal carbonyls, except in cases of extreme steric bulk. The β-triketimines are relatively weak σ-donors, as determined by the CO stretching frequencies in (L)M(CO)3. The molecular structures of the isomorphous pair (L1)M(CO)3 (M = Cr, Mo) reveal porous infinite network arrangements generated by aryl-aryl and CH---OC interactions. The direct reaction of β-triketimines with ZnCl2 in most cases gives [(L)ZnCl]2[Zn2Cl6] complexes, whilst in the presence of either NaBArF4 or AgOTf the corresponding [(L)ZnCl][BArF4] and [(L)ZnCl][OTf] species are obtained. The complexes invariably feature four-coordinate, cationic zinc centres, except in the case of [(η4-L16)ZnCl][BArF4] where a five-coordinate complex is formed by additional coordination of a single ligand methoxy group. The reaction of [(L)ZnCl][BArF4] with TlOEt yielded not the desired zinc alkoxides, but novel [(L)Tl][BArF4] complexes, the solid-state structures of which display thallophilic interactions. The direct reaction of L8 and L10-12 with NiBr2(DME) gives the corresponding four-coordinate [(L)NiBr]2[NiBr4] complexes, whereas the products obtained with weakly-coordinating anions are dependent on the ligand bulk and the size of the anion. With the large BArF4- ion the formation of the five-coordinate dimeric [{(L)Ni(μ-Br)}2][BArF4]2 (L = L1, L3, L5, L7, L8, L12) is strongly favoured, except for the bulkiest ligands where the four-coordinate [(L)NiBr][BArF4] (L = L10, L11) are obtained. The smaller triflate ion generally favours the formation of [(L)NiBr][OTf] (L1, L8, L10-12) except in the case of [{(L)Ni(μ-Br)}2][OTf]2 (L = L3, L5). L15 and L16 act invariably as tetradentate donors to Ni(II), yielding the five-coordinate [(η4-L)NiBr][X] (X = BArF4, OTf) and [(η4-L16)NiBr]2[NiBr4]. The very bulky L6 coordinates in a bidentate mode to Ni(II), giving the four-coordinate [(η2-L6)NiBr(THF)][BArF4] and (η2-L6)NiBr2. [{(L)Ni(μ-Br)}2][BArF4]2 (L = L3, L5, L7), [{(L)Ni(μ-Br)}2][OTf]2 (L = L3, L5), [(η2-L6)NiBr(THF)][BArF4] and (η2-L6)NiBr2 show moderate catalytic activity for the polymerisation of ethylene in combination with MAO. All other complexes tested are inactive, either due to steric factors or the inability of certain β-triketimines to support catalytically active square-planar Ni(II) species. A proposed mechanism for catalyst activation is presented. Elastomeric polyethylene of very low crystallinity is obtained, with branching rates in the range 43-84 branches per 1000 C. 13C NMR spectroscopy reveals the presence of all short-chain branches from methyl to hexyl, as well as longer branches and pairs of branches.

This thesis describes research carried out on the synthesis of lithiation precursors used to investigate the ability of oxazoline activated benzene derivatives to undergo dearomatising cyclisations. Chapter 1 illustrates previous work in the area of dearomatising additions, including intra- and inter-molecular dearomatisations. An overview of relevant work conducted within the Clayden group is also described. Chapter 2 narrates the synthesis of lithiation precursors that contain a (4R,5R)-4,5-diphenyloxazoline activating group on the aromatic ring. The attempts to lithiate and dearomatise these compounds are shown. Chapter 3 describes the synthesis of achiral oxazoline activated O-allylic pre-lithiation substrates, and their ability to undergo dearomatising cyclisations. Also described is the attempts to find a suitable protecting group for N-allylic dearomatising cyclisations. Chapter 4 outlines the investigations carried out for the stereoselective synthesis of (4R,5R)-4,5-diphenyloxazolines, which have been used for the activation towards dearomatising cyclisation. Chapter 5 is an overview of the thesis and outlines possible future work.Chapter 6 contains the experimental methods and data pertaining to Chapters 2 to 5.

On the magnetic criterion, an aromatic system is one that sustains a diatropic ring current. Once this definition is accepted, calculation of current density induced in a molecule by an external magnetic field gives a direct way of determining aromaticity from ab initio calculation. The ipsocentric treatment of molecular magnetic response, in which each point is the origin for the local current-density, offers an accurate, economical and conceptually transparent approach to the calculation of ring currents. The distribution of origin uniquely leads to physically non-redundant orbital contributions· that can be used to interpret (or predict) currents in terms of orbital symmetries, energies and nodal character. Diatropic and paratropic currents obey translational and rotational selection rules, respectively, leading to a 'spectroscopic', 'frontier-orbital' theory of ring currents and magnetic aromaticity. This thesis reports investigations of the nature and origin of ring currents in 1t-, (j- and homo-aromatic systems. Rules developed for annulenes extend to heterocycles and account for retention of ring-current aromaticity in perfluorobenzenes in which argon atoms are progressively inserted in the CF bonds. Currents in benzenoid and nonbenzenoid polycyclic aromatic hydrocarbons give varied patterns which can be rationalised in terms of Kekule structures and Pauling bond orders. These concepts are used to explain rim-and-hub currents in circulenes and design molecules with fully paramagnetic 1t currents, verified by ab initio calculation. Studies of heteropolycycles with carbocyclic cores demonstrate the aromaticity of mellitic trianhydride, the non-aromaticity of 'quasi-rings' closed by hydrogen- and lithium-bonds, and rationalise the magnetic properties of the new 'sulflowers' . Calculations on model rings of silicon atoms with tangential p-p bonding show the possibility of (j ring currents governed by modified versions of the ipsocentric 1t selection rules. Saturated cyclopropane also supports (j ring current. The homotropylium cation illustrates the association of a ring current of modified topology with homoaromaticity.

No description available.

No description available.