published_or_final_version / Chemistry / Master / Master of Philosophy

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This thesis describes synthetic studies directed towards the total synthesis of the natural products TEO3.1, hamigerone and embellistatin. Chapter One provides an overview, which details the role of antifungal natural products in the pharmaceutical and agrochemical industries, and describes the association between total synthesis and natural products. Three structurally related natural products TEO3.1, hamigerone and embellistatin are introduced as synthetic targets and a strategy for their synthesis is proposed involving an intramolecular Diels-Alder (IMDA) reaction, followed by addition-elimination chemistry. Investigations into the application of the IMDA reaction to the synthesis of the bicyclic core are described in Chapter Two. A Julia olefination reaction was used to install the diene moiety and allowed for the successful synthesis of a model triene precursor. The IMDA cyclisation of the triene was shown to proceed with high endo-selectivity. However, efforts to generate the diene-containing bicyclic core failed and, as a result, this approach to the natural products was abandoned. Chapter Three introduces the diene-regenerative Diels-Alder reaction as an alternative strategy for the direct installation of the diene moiety. The preparation of a model system is described, which established methodology for the efficient preparation of the pyrone-containing Diels-Alder substrate. Cyclisation of this material via a [4 + 2] cycloaddition reaction, followed by extrusion of carbon dioxide, proved a viable method for generating the desired cyclohexadiene system. In Chapter Four, the previously established methodology is applied to the synthesis of the fully functionalised bicyclic core of TEO3.1, hamigerone and embellistatin. The preparation of the racemic Diels-Alder substrate and its successful cyclisation to the bicyclic core is described. An investigation into the preparation of chiral material is also discussed, as well as the description of a model study for the installation of the various side-chains of the natural products. The chapter concludes with a brief discussion of the future studies required to complete the total synthesis of the TEO3.1, hamigerone and embellistatin.

Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

Nitroacrylates are stable, crystalline solids and have frequently been used in synthesis as reactive dienophiles in the Diels-Alder reaction. The regio- and diastereoselectivity of the Diels-Alder reaction is controlled by the electronic properties of the nitro group. This thesis describes work to utilise the nitro group to provide control of stereochemistry in the synthesis of natural products. The thesis begins by discussing the synthesis of nitroacrylates using both a nitro-aldol and radical based route. An investigation into their selectivity in the Diels-Alder reaction with a diverse array of dienes is discussed. As part of this investigation a large increase in diastereoselectivity was observed for the reaction of ethyl β-nitroacrylate and 1-methoxycyclohexa-1,4-diene when Lewis acids were added. The origin of this selectivity is unknown and similar dienes show only a modest increase in selectivity on addition of ZnCl(_2).An application of the resultant adducts has been demonstrated in the synthesis of a simple bicyclic P-amino acid and then subsequendy applied to the diastereoselective synthesis of chorismate-based P-amino acids (25*, 3S*)-DHAA and the antibiotic oryzoxymycin. The key steps involve a base-mediated ring-opening reaction of the 7-oxa-bicyclo[2,2,l]hept-5-ene and a CsF mediated coupling of the lactate moiety. The progress toward the synthesis of a related anthranilate synthase inhibitor is also discussed. Finally, in the context of a synthesis of the structurally unique diterpene Vinigrol 1 we have shown that nitroacrylates can be employed as substituted ketene equivalents in the formation of cyclic alpha-chiral ketones.

This thesis describes synthetic studies directed towards the total synthesis of the natural products TEO3.1, hamigerone and embellistatin. Chapter One provides an overview, which details the role of antifungal natural products in the pharmaceutical and agrochemical industries, and describes the association between total synthesis and natural products. Three structurally related natural products TEO3.1, hamigerone and embellistatin are introduced as synthetic targets and a strategy for their synthesis is proposed involving an intramolecular Diels-Alder (IMDA) reaction, followed by addition-elimination chemistry. Investigations into the application of the IMDA reaction to the synthesis of the bicyclic core are described in Chapter Two. A Julia olefination reaction was used to install the diene moiety and allowed for the successful synthesis of a model triene precursor. The IMDA cyclisation of the triene was shown to proceed with high endo-selectivity. However, efforts to generate the diene-containing bicyclic core failed and, as a result, this approach to the natural products was abandoned. Chapter Three introduces the diene-regenerative Diels-Alder reaction as an alternative strategy for the direct installation of the diene moiety. The preparation of a model system is described, which established methodology for the efficient preparation of the pyrone-containing Diels-Alder substrate. Cyclisation of this material via a [4 + 2] cycloaddition reaction, followed by extrusion of carbon dioxide, proved a viable method for generating the desired cyclohexadiene system. In Chapter Four, the previously established methodology is applied to the synthesis of the fully functionalised bicyclic core of TEO3.1, hamigerone and embellistatin. The preparation of the racemic Diels-Alder substrate and its successful cyclisation to the bicyclic core is described. An investigation into the preparation of chiral material is also discussed, as well as the description of a model study for the installation of the various side-chains of the natural products. The chapter concludes with a brief discussion of the future studies required to complete the total synthesis of the TEO3.1, hamigerone and embellistatin.

Zugl.: Basel, Univ., Diss., 2007

Universiẗat-Gesamthochsch., Diss.--Paderborn, 1998.

Thesis (Ph.D.) - University of St Andrews, June 2007. / Restricted until 20th June 2009.

Thèses (M.Sc.)--Université de Sherbrooke (Canada), 2000. / Titre de l'écran-titre (visionné le 20 juin 2006). Publié aussi en version papier.