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In connection with our long-standing interest in the chemical constituents of Formosan octocorals, we have investigated the octocorals Briarium excavatum and Junceella fragilis, collected at southern Taiwan coast. During the investigation, four new metabolites brianthiens D‐G (1‐4), have been isolated from Briareum excavatum. In addition, four 11,20-epoxybriaranes including three new metabolites, fragilides B‐D (5‐7), along with a known briarane (¡V)-11£\,20£\-epoxy-4-deacetoxyjunceellolide D (8), have been obtained from J. fragilis. The structure of 8 was revised as (¡V)-11£],20£]-epoxy-4-deacetoxyjunceellolide D (8) by detailed spectral data analysis. The structures, including the relative configurations of the new briaranes 1‐7, were elucidated by spectroscopic methods. The structure of fragilide B (5) was further confirmed by X-ray diffraction analysis. The relationship between 13C NMR chemical shifts and conformation of the cyclohexane ring in briaranes possessing 11,20-epoxy group, are also described.

The development of methods for site-selective derivatization of natural products to enable simultaneous arming and structure activity relationship (SAR) studies has shown great potential for the synthesis of pharmaceutical drug leads and cellular probes for mechanism of action studies. Herein, we describe a strategy to functionalize carboxylic acid and phenol containing natural products. This methodology relies on the in situ generation of diazoalkanes to form the corresponding carbonyl esters and phenolic ethers derived from natural products. We applied this process to several natural products, to begin demonstrating the utility of this methodology for the simultaneous arming and SAR studies of natural products. To expand our group’s nucleophile catalyzed aldol lactonization (NCAL) reaction for synthesizing highly substituted cyclopentane fused beta-lactones, we developed a nucleophile catalyzed, tandem Michael aldol lactonization (NCMAL) reaction. Herein, we show the synthetic utility of this reaction in varying the Michael donors and acceptors, developing a catalytic, enantioselective NCMAL, and synthesizing tricyclic-!-lactones. Furthermore, we initiated studies toward applying this new methodology to the synthesis of a lipase inhibitor, vibralactone.

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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.

In the thesis, the development of asymmetric organocatalytic [3+3] sequences for the assembly of aminocyclitols is described. A water-based Wittig reaction was developed in order to produce the key enal-based starting materials, which were otherwise difficult to obtain commercially and synthetically. The enals derived from the Witig reaction were employed in the synthesis of both natural products and synthetic analogs of compounds in the amaryllidaceae family. The [3+3] Michael-aldol sequence described herein provided regio-, diastereoand enantioselective access to the core of the various targeted molecules, containing 3 to 4 defined stereocenters. The sequence was optimized via manipulation of the structures of both the organocatalyst and base used leading to increased selectivity and yield. Complete total synthesis of the natural product (+)-trans-dihydrolycoricidine was achieved using the optimized organocatalytic Michael-aldol sequence. The most effective catalyst/base combination for this synthesis was found to be a comercial diphenylsilylprolinol ether and quinidine, which led to a dramatic reduction in the number of synthetic steps taken to the final product, and highest yield, when compared to other reported approaches: in 9 chemical steps, 12% overall yield and 98% e.e. were achieved. Two non-natural analogues were also synthesized using this methodology in order to probe the minimum pharmacophore of the amaryllidaceae derivatives, as they are known to express anti-viral and anti-cancer activity for certain cell lines. (+)-3- Deoxydihydrolycoricidine containing 4 chiral centers, was synthesized via the same [3+3] Michael-aldol sequence as the natural product in 6 steps with 15% yield and >99% e.e. Similarly, (+)-trans-3-epidihydrolycoricidine was obtained in 6 steps, 27% yield and >99% e.e. The biological activity of these derivatives is yet to be examined. This highly effective method for the preparation of chiral aminocycllitols can be generalized toward the synthesis of numerous targets, which will be the focus of future research. / Thesis / Doctor of Philosophy (PhD)

A highly convergent strategy for the synthesis of the antitubulin polyketide disorazole C1 is proposed based around the alkyne precursor I, featuring a novel Evans-Tishchenko/ring closing alkyne metathesis approach. Due to the inherent symmetry of the molecule this retrosynthesis leads to two fragments: a β- hydroxyketone II and the oxazole C(1)-(9) fragment III. A review of previous syntheses of disorazole C1 and established structure activity relationships (SARs) highlights a gap in current knowledge relating to the role of the oxazole in tubulin binding. Therefore, the focus of this research has been towards developing new routes for the synthesis of the C(1)-C(9) fragment that can be adapted to the synthesis of heterocyclic analogues to further establish the SAR of disorazole C1. Chapter 2 focuses on a disconnection at the C(5)-C(6) bond and a novel synthesis of the racemic C(1)-C(9) fragment has been achieved via a lithiation of methyl 2- methyl-1,3-oxazole-4-carboxylate and coupling to aldehyde V. First generation asymmetric routes to the C(1)-C(9) fragment centred on i. a biomimetic amino acid condensation route via an oxazoline intermediate based on the precedent of Meyers et al. and ii. a C(4)-C(5) disconnection approach based around the epoxide VII; are discussed in chapter 3. A second generation C(4)-C(5) disconnection centred on the novel tosylate VIII is discussed in chapter 4. Attempts to synthesise the parent C(1)- C(9) oxazole fragment using the tosylate VIII via i. a palladium catalysed C-H activation of ethyl 4-oxazole carboxylate and ii. lithiation of oxazole are reported. Coupling of fragment VIII (X = OTs) with ethyl 1H-pyrazole-4-carboxylate and a CuAAC coupling of the azide derived from tosylate VIII with methyl propiolate has allowed the successful completion of the synthesis of pyrazole and triazole analogues of this fragment.

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No description available.