Bochum, Universiẗat, Diss., 2002.

No description available.

The research presented herein is concerned with the exploration of tandem processes initiated by the conjugate reduction of Michael acceptors, encompassing the asymmetric reductive Dieckmann reaction and the two-carbon homologation of aldehydes by two complementary methodologies. Chapter 1 introduces the area of transition metal catalysed tandem reductive processes as a tool for carbon-carbon bond formation. An extensive discussion of this methodology is included and recent advances in the area are highlighted. Chapter 2 discusses the initial study into the asymmetric reductive Dieckmann condensation. 3,3’-Disubstituted 4-oxopyrrolidines were synthesised in up to 93% ee using both molybdenum and copper catalysis. Chapter 3 describes the novel molybdenum-catalysed two-carbon homologation of aldehydes by the reduction of alkylidene Meldrum’s acid derivatives. No over reduction to the corresponding alcohol is observed, as the aldehyde functionality remains protected until hydrolysis. Chapter 4 discusses the mild, expeditious amine promoted reduction of cyclic malonates to β-substituted propionaldehydes. The synthetic utility of the methodology is demonstrated by the synthesis of γ-substituted propylamines in a one-pot hydrosilylation/reductive amination process. Chapter 5 describes the synthesis and characterisation for the compounds discussed in chapters 2, 3 and 4.

Polypropionate marine natural products have emerged as a class of compounds that display a high degree of structural diversity. Specifically, metabolites such as that reported as tridachiahydropyrone (7), isolated from sacoglossan molluscs, display novel ring systems. The introductory chapter gives some background on tridachione marine natural products and outlines the isolation of metabolites from several species of sacoglossan mollusc. Chapter One also gives examples of the utility of the tandem conjugate addition-Dieckmann condensation approach being applied to the synthesis of these compounds. Chapter Two describes the development of the tandem conjugate addition-Dieckmann condensation and subsequent trans methylation approach to cyclohexenone rings. The synthetic strategy utilised chiral, functionalised cyclohexenone rings as synthons in the formation of bicyclic ring systems, so development of the carbocyclic ring formation was of vital importance to the overall strategy. Examples are given which confirm the viability of the proposed synthetic route to cyclohexenones such as 91, 92 and 104 from the reaction of [alpha,beta]-unsaturated carbonyl compounds 39 and 59 with dialkyl and dialkenyl Gilman cuprates. Chapter Three describes the incorporation of chiral cyclohexenone 117 into the bicyclic framework of model compound 105, analogous to the marine natural product reported as tridachiahydropyrone (7). The chapter explores the use of cyclohexenone precursor 43 that contained the total carbon framework of the bicyclic core of the desired pyrone. Once again, a tandem conjugate addition-cyclisation reaction was employed using a dialkyl Gilman cuprate, followed by trans methylation to give the requisite cyclohexenone synthon 117. A novel Eaton’s reagent-promoted intramolecular cyclisation of acid 122 to pyrone 123 was then effected. Subsequent O-methylation afforded [alpha]-methoxy-[beta]-methyl-[gamma]-pyrone 105 as a single enantiomer, which had the identical core structure to the natural product. The structure, including relative stereochemistry of 105, was confirmed by single crystal X-ray analysis. Chapter Four builds on the previous two chapters and describes the conjugate addition-cyclisation with a higher order Gilman cuprate derived from vinyl bromide 44, which would deliver the vinyl side-chain required for the synthesis of reported natural product 7. The same acyclic precursor 43 as used in Chapter Three was cyclised and methylated to yield yet another cyclohexenone synthon 41. A single crystal X-ray analysis of related alcohol 162 confirmed the relative stereochemistry and structure. Another novel P2O5-mediated intramolecular cyclisation was achieved to give pyrone 168 and O-methylation provided a compound with the reported structure of natural product 7 as a single enantiomer. The structure of synthetic 7 was established unequivocally through extensive NMR studies. Comparisons of spectral data confirmed that natural tridachiahydropyrone was not the same as synthetic compound 7, so revision of the assigned natural product structure is warranted. Several other analogues were also synthesised using this methodology, highlighting the versatility of the method under development.

Plusieurs pigments de champignons, tels que la norbadione A et des dérivés de l'acide pulvinique, ont révélé une activité antioxydante remarquable. Au cours de cette thèse, nous nous sommes intéressés à la synthèse de ces composés qui pourraient être employés comme agents de protection contre les rayonnements ionisants. Dans ce contexte, une nouvelle voie d'accès à des dérivés de l'acide tétronique a été mise au point à partir d'arylacétates de méthyle et d'hydroxyesters. La méthodologie développée a permis, en une seule étape, la synthèse de plusieurs acides 3-aryltétroniques et de composés hétérocycliques apparentés. A partir d'un dérivé de l'acide tétronique, trois esters d'acides pulviniques naturels ont été préparés par une voie très directe et avec de bons rendements. Dans le cadre de la synthèse totale de la norbadione A, deux voies de synthèse ont été étudiées. La première consiste à appliquer la méthodologie développée au cours de cette thèse pour la synthèse d'acides pulviniques. Les travaux réalisés ont ainsi permis la synthèse d'un intermédiaire avancé. La seconde voie, dont l'étape clé est un double couplage de Suzuki-Miyaura, a conduit à la première synthèse totale de la norbadione A.

La recherche constante de nouvelles stratégies pour la construction de liaisons carbone-carbone et le désir d’imiter la nature dans son extraordinaire habileté à former des polycycles complexes nous ont mené à étudier la réaction de polycyclisation anionique. Jouant sur des modifications autour d’une structure de type sorbate, divers précurseurs ont pu être synthétisés en vue d’une cascade réactionnelle. Parmi ceux-ci, les précurseurs possédant une fonction malonate ont efficacement mené à la formation de polycycles fonctionnalisés, au travers d’une séquence tandem d’oléfination de Horner-Emmons suivie immédiatement d’une polycyclisation anionique incluant une addition de Michael intramoléculaire et une condensation de Dieckmann. Enfin, l’étude d’une variante pour rendre la séquence plus polyvalente a été débutée. Celle-ci se base sur l’initiation de la cascade réactionnelle par une addition de Michael intermoléculaire.

Since the middle of the 20th century, significant interest has evolved from the scientific community towards the polypropionate family of marine natural products. A number of these compounds have been shown to possess significant biological activity, and this property, as well as their structural complexity, has driven numerous efforts towards their synthesis. The first chapter provides an introduction into the world of polypropionates, with a discussion on synthetic studies into a number of members of the tridachiapyrone family. Fundamental synthetic concepts utilised in this thesis towards the preparation of polyketides are also described, with a focus on their application towards the synthesis of 9,10-deoxytridachione, anti tridachiahydropyrone and syn tridachiahydropyrone. Chapter 2 describes the work undertaken towards the total synthesis of 9,10-deoxytridachione. The novel tandem conjugate addition-Dieckmann condensation of complex enones developed previously in the Perkins group was used to generate anti methylated cyclohexenones as key synthetic intermediates. The conversion of the cyclohexenones into the corresponding cyclohexadienes via allylic alcohols was attempted, utilising a Grignard-mediated reaction to achieve the selective 1,2-reduction. Studies into the Grignard-mediated reduction were also undertaken on seven additional cyclohexenones, in order to investigate the utility and scope of the reaction. The extension of the methodology previously developed for the synthesis of cyclohexenones is the subject of Chapter 3. This section describes investigations into the synthesis of stereochemically-diverse cyclohexenones from complex enones. The conjugate addition-Dieckmann condensation strategy was extended successfully towards the synthesis of a syn methylated cyclohexenone, which allowed the synthesis of the proposed true structure of tridachiahydropyrone to be pursued. The methodology developed in Chapter 3 was utilised in Chapter 4 to synthesise a model system of syn tridachiahydropyrone. A comparative analysis of the NMR data of the syn model, an anti model and anti tridachiahydropyrone with the natural product indicated that the true structure of tridachiahydropyrone may indeed have syn stereochemistry. The synthesis of syn tridachiahydropyrone was attempted, and to this end a suitable cyclohexanone was successfully synthesised. However, the subsequent methylation-elimination cascade failed to furnish the desired syn methylated cyclohexenone, producing only an anti methylated cyclohexanone. The stereochemistry of the methylation was deduced using high and low variable temperature NMR coupled with selective irradiation NOESY.

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第18210号 / 薬博第800号 / 新制||薬||237(附属図書館) / 31068 / 京都大学大学院薬学研究科創薬科学専攻 / (主査)教授 川端 猛夫, 教授 竹本 佳司, 教授 高須 清誠 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DGAM