Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xviii, 211 p.; also includes graphics Includes bibliographical references (p. 128-134). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Ohio State University, 2002. / Title from first page of PDF file. Document formatted into pages; contains xiv, 242 p.). Includes abstract and vita. Advisor: Leo A. Paquette, Dept. of Chemistry. Includes bibliographical references (p. 233-242).

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trans-2,5-Disubstituted tetrahydrofurans (THFs) are a common structural motif in a multitude of biologically active natural products. This thesis explores new synthetic routes for their synthesis and subsequent application towards the C_31-40 fragment of pectenotoxin-4. <b>Chapter 1: Introduction</b> This chapter reviews methods for the synthesis of trans-2,5-disubstituted tetrahydrofurans with a special emphasis on those that have been applied towards the synthesis of natural products. <b>Chapter 2: Results and Discussion</b> The Acyloin Coupling Reaction towards trans-THFs A brief overview of the acyloin coupling reaction is followed by description of the aim for this part of the project, using this process as a key step towards trans-THFs. Work directed towards the stereoselective protonation of the bis-enolate intermediate formed during the acyloin coupling is discussed. The exploitation of A^1,3 strain was the most effective strategy found to control the diastereoselectivity in the protonation of the bis-enolate intermediate. Desymmetrisation Using Sharpless Asymmetric Epoxidation towards trans-THFs Strategy developed towards the synthesis of a 2,5-disubstituted 3-hydroxy trans-THF is studied. The optimisation of the synthesis of meso-hepta-1,6-diene-3,5-diol was examined and subsequent desymmetrisation using the Sharpless asymmetric epoxidation was explored. Approaches towards the FG Fragment of Pectenotoxin-4 The previous synthesis of the FG fragment was reviewed. Details of the retrosynthesis to be employed for the preparation of the southern hemisphere of pectenotoxin-4 are discussed. The desymmetrisation strategy previously explored was applied towards forming the F ring of pectenotoxin-4. The C_31-40 carbon skeleton was successfully formed in 12 steps using a convergent synthesis. The elucidation of an X-ray crystal structure requires further exploration to confirm the relative and absolute configuration of the THF formed. <b>Chapter 3: Experimental</b> Full experimental procedures and characterisation of compounds are reported.

This thesis explores new synthetic routes for the formation of CDE & EFG fragments of pectenotoxin-4. Chapter 1: Introduction and Previous Work: This chapter reviews the discovery and biological activities of members of the pectenotoxin family. Two previous total syntheses are discussed, and previous work regarding the synthesis of ABC, E and FG fragments within the group is introduced. Chapter 2: Synthesis of the E Ring Fragment of Pectenotoxin-4: The synthesis of the E ring fragment is discussed. Key reactions include Negishi coupling and osmium mediated oxidative cyclisation. Chapter 3: First Generation Strategy for the Synthesis of the D ring: A simple model towards the D ring core was completed using alkyne-epoxide opening strategy. The application on a more sophisticated system was tested. Chapter 4: Second Generation Strategy for the Synthesis of the D ring: Sonogashira coupling was successfully tested as key step to unite two coupling partners; and further functionalisation towards the D ring skeleton was studied. Chapter 5: Third Generation Strategy for the Synthesis of the D ring: The new strategy including a Lewis acid assisted coupling and mercury mediated hydration of alkyne sequence was completed on a simple model. The application on a more sophisticated system was tested. Chapter 6: Synthesis of EFG Fragment of Pectenotoxin-4: Key Julia-Kocienski olefination between E ring fragment and FG ring fragment was examined. The further functionalisation of the resulting coupling product towards EFG fragment was finished. Chapter 7: Experimental: Full experimental procedures and characterisation of compounds are reported.

The acid-mediated osmium-catalysed oxidative cyclisation of 1,2-diols bearing a pendent alkene has been shown to be a powerful method for the formation of cis-2,5-disubstituted tetrahydrofurans. This thesis describes the development of this methodology to broaden the scope of the general reaction, followed by applying the oxidative cyclisation to the synthesis of tetrahydrofuran containing natural products. Introduction: This section reports a range of ractions that osmium oxo-species will facilitate, namely the formation of carbon-oxygen and carbon-nitrogen bonds in a selective manner. In addition to this a variety of similar metal-mediated oxidative cyclisations are discussed. Results and Discussion: The process for optimising the oxidative cyclisation is documented, along with examples which directly compare newly developed methodology with existing methodology. The incorporation of a catalytic amount of a Lewis acid is shown to be more effective than using an excess of a Brønsted acid, with osmium catalyst loading being reduced to 0.2 mol%. Subsequently, this methodology is shown to facilitate the successful oxidative cyclisation of vinyl silanes to form silyl-substituted tetrahydrofurans, along with methodology to “unmask” the silane, as a potential route to lactols. Finally, the application of this methodology to synthesis is demonstrated, with the successful synthesis of neodysiherbaine A being achieved in 7 steps and the C21-30 fragment of pectenotoxin-4 in 12 steps.

The cobalt-catalysed oxidative cyclisation of 5-hydroxy alkenes has been demonstrated to be a powerful synthetic tool for the formation of trans-THFs with excellent diastereoselectivity. This thesis describes the utilisation of this methodology in the synthesis of the FG fragment of pectenotoxin-4, allowing the scope of the reaction to be further explored. Introduction: This section introduces the pectenotoxins, a family of structurally complex closed-chain polyether macrolides with promising biological activities. The isolation, structural elucidation, and biological properties of the pectenotoxins are reviewed, along with a summary of previous syntheses towards the FG fragment of pectenotoxin-4. In addition, the cobalt-catalysed oxidative cyclisation of 5-hydroxy alkenes and its application in synthesis is discussed. Results and Discussion: An outline of the synthetic strategy employed in this project and details of the novel retrosynthesis of the C31-C40 fragment of pectenotoxin-4 is described. The synthetic studies carried out towards the synthesis of the FG fragment of pectenotoxin-4 are discussed in detail, with the exploitation of a cobalt-catalysed oxidative cyclisation as the key step to form the trans-THF F-ring. Overall, the FG fragment, which contains six stereogenic centres, was achieved in 18 total synthetic steps (13 longest linear sequence).

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This thesis details the application of two synthetic methodologies, developed by the Donohoe group, to the synthesis of the ABC fragment of pectenotoxin-4, a macrolide marine natural product that consists of 19 stereogenic centres, three tetrahydrofuran rings, one spiroketal and one bicyclic ketal embedded within a 26-membered macrocycle. Pivotal to the developed synthetic route was the utilisation of an unprecedented cascade osmium catalysed oxidative cyclisation for the construction of two THF rings (the BC ring system). After successfully developing a model system for the synthesis of the AB anomeric 6,5 spiroketal, which involved the employment of a hydride shift initiated oxo carbenium ion formation followed by intramolecular spiroketalisation, the developed system was then applied to the fully elaborated synthesis of the ABC fragment. The synthesis of the ABC fragment of pectenotoxin-4 was completed in 20 linear steps, with an overall yield of 3.3%.