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The chivosazoles, isolated in 1994 from the myxobacterium Sorangium cellulosum by Höfle and co-workers, are a family of polyketides that exhibit a range of potent biological activity including antifungal and cytoxicity against human cancer cell lines. This thesis details studies towards the total synthesis of the chivosazoles. Chapter 1 discusses the isolation, characterisation and biological activity of these compounds, as well as the first total synthesis of chivosazole F (12) by the Kalesse group. Chapter 2 describes the development of a highly convergent approach to assemble the chivosazoles from three key fragments A (69), B (70) and C (71), of similar size and complexity. A flexible endgame coupling of these fragments is proposed via a Stille- Suzuki-macrolactonisation or Stille-esterification-Suzuki sequence. The first generation route to access fragment A is described, utilising Paterson 1,4-syn boron aldol methodology and an Evans-Tishchenko 1,3-anti reduction to define the stereochemistry. The relative configuration of this subunit, as proposed by Kalesse, was independently confirmed by synthesis of C28-C35 degradation fragment 21. The C19-C22 stereotriad featured in fragment B was installed, again, using a boron-mediated aldol reaction followed by an Evans-Tishchenko reduction. The required oxazole moiety was formed via a Williams-Wipf cyclisation procedure. Having prepared fragments A and B, coupling conditions were established to form the northern hemisphere subunit and the NMR data of this region correlated favourably with that of the natural product. Chapter 3 describes the second-generation route to fragment A (69), featuring fewer steps and improved scalability for preparation of multi-gram quantities of this material. Different strategies for modification of the functional group at C16 on the oxazole ring for planned coupling with fragment C (71) were explored. Unexpected difficulties with the installation of this coupling handle are outlined, as well as a modification to our oxazole-formation strategy to overcome these challenges. As an alternative to eventual esterification or macrolactonisation at C1, Still-Genarri and Ando olefinations were investigated on model systems for formation of the C2-C3 (Z)-olefin. Advanced C7-C35 fragments are constructed via subsequent Stille cross-couplings in preparation for formation of the macrolactone core of the chivosazoles. Chapter 4 outlines three potential highly-convergent endgame strategies for ongoing studies. The experimental procedures and spectroscopic characterisation of the compounds discussed are found in Chapter 5 and the Appendix.

Structure-activity relationships (SARs) in the disorazole family have been revealed through the biological testing of natural disorazoles and their synthetic analogues, but little is known about the contribution of the oxazole to the anti-tubulin activity of disorazole C1 I. The development of a novel Evans-Tishchenko/alkyne metathesis (ET-AM) route towards the synthesis of disorazole C1 will provide straightforward access to disorazole C1 and its heterocyclic analogues, thus allowing the contribution of the oxazole to the natural product's bioactivity to be elucidated. Our ET-AM approach offers a highly diastereoselective and convergent means of constructing heterocyclic analogues of the disorazole C1 scaffold Het-II. It is envisaged that ET coupling of C(1)-C(9) aldehydes Het-IV to the C(10)-C(19) β-hydroxyketone V will give the key, requisite, 1,3-anti diol monoester bis-alkynes Het-III for dimerisation via an alkyne cross-metathesis/ring-closing alkyne metathesis (ACM-RCAM) reaction. Further diversification may be achieved through the synthesis of C(6)-heteroatom analogues of the C(1)-C(9) fragment Het-IV. Chapter 2 outlines efforts towards the synthesis of C(6)-amino analogues Het-VI of the C(1)-C(9) fragment IV. Elaboration of Garner's aldehyde VIII allowed the synthesis of the N-protected C(5)-C(9) mesylate VII; an analogue of an advanced C(1)-C(9) fragment intermediate. A scalable route towards the synthesis of the C(10)-C(19) fragment V and investigations into its reactivity under ET coupling conditions are critical to the success of our ET-AM approach. Chapter 3 details convergent approaches towards the synthesis of the C(10)-C(19) β-hydroxyketone V, which centred around: (i) an olefin cross-metathesis reaction [C(11)-C(12) disconnection]; (ii) an epoxide ringopening reaction [C(12)-C(13) disconnection]; and (iii) a Mukaiyama aldol reaction [C(14)-C(15) disconnection]. Chapter 4 describes our successful linear synthesis of the β-hydroxyketone V. Gram-scale preparation of the C(10)-C(19) fragment V permitted investigation into the viability of the ET reaction as a fragment coupling strategy, the results of which are reported in Chapter 5. Although many (hetero)aryl aldehydes failed to react, the successful coupling of electron-deficient substrates allowed a contingency strategy to be explored through preparation of the mono-protected diol IX. Esterification of IX with the carboxylic acid derivative of the C(1)-C(9) oxazole has allowed generation of the C(1)-C(9)/C(10')-C(19') bis-alkyne X required for future AM investigations.

1. We have explored a formal [3+2] strategy that is synthetically useful for constructing 3,4-disubstituted succinimides with ethyl bromoacetate derivatives or methyl glyoxylate in one step. 2. We reported a new approach to (E)-£]-aryl-£\,£]-unsaturated amides. Instead of using aldehydes, phosphorus, silicon containing compounds and metal catalysts for the synthesis of double bonds, £\-sulfonyl acetamide and various benzyl bromides were used as starting materials

New Carbanion Rearrangement of Sulfur Compounds and Its Application Abstract This thesis reports the investigation of an unusual reversal in the metalation selectivity of alkyl aryl sulfones and sulfoxides and its application. Such compounds undergo initial directed ortho-metalation at −78 řC despite having an acidic α-hydrogen atom and the resulting aryllithiums rearrange subsequently completely to the initially expected α-sulfonyllithiums on warming. The scope and the limitations for this process were identified. Both carbanion types of sulfones were applied in reactions with various electrophiles. α-Lithiated sulfones generated upon the transmetalation process were used in Julia olefinations. A mechanistic study of the course of the transmetalation reaction is presented. The kinetics of the transmetalation were determined. Investigations concerning the concentration dependence, proton transfer equilibria between the different ortho-sulfonyllithium intermediates and crossover experiments provided the evidence that a concerted intermolecular pathway prevails. On this basis a new integrated synthetic approach to naturally occurring iridoids was developed. It is based on a tandem alkoxycarbonylation/oxidative radical cyclization of the olefins synthesized by the Julia reaction after the investigated...

This thesis describes tin and non-tin mediated approaches towards the total synthesis of chaetochalasin A 1 through an intramolecular domino Diels-Alder approach, and subsequent synthesis of the Diels-Alder analogues exo NH 13E-272, endo NH 13E-273, exo NH 13Z-287 and endo NH 13Z-288 through an intramolecular Diels-Alder approach.The initial tin mediated route involved the initial formation of alcohol 119, which exhibited a 2,4-syn methyl arrangement, put in place through the use of two chiral auxiliary mediated asymmetric alkylations. Subsequent functionalisation of alcohol 119 led to aldehyde 215, which incorporated a vinyl stannane functional group. The α,β-unsaturated aldehyde 215 was then reacted with β,γ-BT-sulphone 120 under trans selective Julia conditions to give predominantly the (1E,7E,9E,11E) isomer of vinyl stannane 117. However, subsequent Stille reactions to form the Z,E diene functional group, between vinyl stannane 117 and vinyl iodide 118 resulted in a product that exhibited extreme isomerisation of the triene functional group.A subsequent non-tin mediated route involved the synthesis of aldehyde 229 from alcohol 119, which then underwent a trans selective Julia olefination with BT-sulphone 120 to give predominantly the (2E,8E,10E,12E) isomer of ester 228. Ester 228 was then converted into aldehyde 227, which then underwent a Z-selective olefination to put in place the 2Z,4E diene of methyl ester 226. Further functionalisation of methyl ester 226 using past methodology within the Thomas group led to pyrrolinone 110. Subsequent small scale attempts to convert pyrrolinone 110 into chaetochalasin A 1 through a domino Diels-Alder reaction proved ineffective.Formation of the exo NH 13E-272, endo NH 13E-273, exo NH 13Z-287 and endo NH 13Z-288 Diels-Alder analogues involved the initial conversion of alcohol 119 into aldehyde 275, followed by trans selective Julia olefination with BT-sulphone 120 to give predominantly the (4E,10E,12E,14E) isomer of ester 274. Further functionalisation of ester 274 using past methodology within the Thomas group, led to pyrrolinone 243, which then underwent an intramolecular Diels-Alder reaction to give the 13E : 13Z isomers in a 1 : 1 ratio, with each isomer exhibiting an exo : endo geometry in a 5 : 4 ratio.