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Chapter 1 details our investigation into the Diels-Alder reaction between arynes and chiral furans and pyrroles for the synthesis of unsymmetrical [2.2.1] oxabicyclic and azabicyclic scaffolds as single enantiomers. It was discovered that the diastereoselectivity of the aryne Diels-Alder reaction was sensitive to conformational effects that could be exploited to obtain both high yields and dr. Stereoselective synthesis using arynes is an overlooked field, and this contribution represents one of only three such examples in the literature. The desymmetrization of meso [2.2.1] oxabicyclic systems by intramolecular cyclization/ring- opening was studied, and a cationic Rh/t-Bu-Josiphos catalyst was developed that delivered polyclic dihydronaphthalene products in excellent yield and ee. These catalyst conditions were used for the ring-opening of an enantiomerically pure unsymmetrical oxabicyclic alkene, which led to the discovery that ring-opening proceeded with complete reagent control. A regiodivergent resolution was designed that gave pairs of enantiomerically enriched dihydronaphthalenes from unsymmetrical racemic starting materials. In chapter 3, the scope of the regiodivergent resolution was expanded to include the ring-opening of remotely-substituted oxabicyclic alkenes and furan-hetaryne Diels-Alder adducts. The utility ii of the method was demonstrated by using it to synthesize two important API molecules from a single racemic precursor. Finally, chapter 4 describes our lab’s efforts toward the total synthesis of the natural products phorbol and prostratin that features the ring-opening of an unsymmetrical [3.2.1] oxabicycle as the key step. Advanced intermediates (requiring >30 linear steps) were synthesized on gram- scale. The entire carbon framework was successfully installed, and our efforts to complete the synthesis are discussed.

Chapter 1 details our investigation into the Diels-Alder reaction between arynes and chiral furans and pyrroles for the synthesis of unsymmetrical [2.2.1] oxabicyclic and azabicyclic scaffolds as single enantiomers. It was discovered that the diastereoselectivity of the aryne Diels-Alder reaction was sensitive to conformational effects that could be exploited to obtain both high yields and dr. Stereoselective synthesis using arynes is an overlooked field, and this contribution represents one of only three such examples in the literature. The desymmetrization of meso [2.2.1] oxabicyclic systems by intramolecular cyclization/ring- opening was studied, and a cationic Rh/t-Bu-Josiphos catalyst was developed that delivered polyclic dihydronaphthalene products in excellent yield and ee. These catalyst conditions were used for the ring-opening of an enantiomerically pure unsymmetrical oxabicyclic alkene, which led to the discovery that ring-opening proceeded with complete reagent control. A regiodivergent resolution was designed that gave pairs of enantiomerically enriched dihydronaphthalenes from unsymmetrical racemic starting materials. In chapter 3, the scope of the regiodivergent resolution was expanded to include the ring-opening of remotely-substituted oxabicyclic alkenes and furan-hetaryne Diels-Alder adducts. The utility ii of the method was demonstrated by using it to synthesize two important API molecules from a single racemic precursor. Finally, chapter 4 describes our lab’s efforts toward the total synthesis of the natural products phorbol and prostratin that features the ring-opening of an unsymmetrical [3.2.1] oxabicycle as the key step. Advanced intermediates (requiring >30 linear steps) were synthesized on gram- scale. The entire carbon framework was successfully installed, and our efforts to complete the synthesis are discussed.

Studies directed toward the total synthesis of the cytotoxic steroidal alkaloid cortistatin A were carried out. In a model system, it was determined that a sequence of reactions involving a lithiocyclopropene addition-intramolecular [4 + 2] cycloaddition cascade and subsequent cyclopropylcarbinyl rearrangement allowed for ready access to the BCD rings of the core steroid. Implementation of this methodology en route to the fully functionalized natural product proved an effective means for the elaboration of the A ring carbocyclic framework. / text

The patellazoles are a family of marine polyketide natural products first isolated from Lissoclinum patella in 1988 by both the Moore and Ireland groups. They exhibit significant cytotoxicity against the HCT 116 human colon tumour cells. To date however, their full 3D stereostructure have yet to be elucidated, which has hindered their development as potential drugs, and hampered full investigation into their biological mechanism of action and has deterred total synthesis efforts. This thesis describes synthetic efforts towards Patellazole B, which exhibits the highest potency of the three main congeners. To fully elucidate the structure and renew interest in the patellazoles as anticancer compounds, we have developed a flexible and modular synthesis that aims to define the unknown stereocentres within the pertinent region and allow for rapid fragment union. Compound 36 has been chosen as an initial target for NMR comparison studies. The synthesis of all eight diastereomers of this macrocycle should aid determination of the four unknown stereocentres. Chapter 2 describes the synthesis of the C1–C12 fragment, focusing on the configuring of the C5 methyl stereocentre and the construction of the C7-C10 stereotetrad via a boron-mediated anti aldol with an in-situ reduction. In the third chapter, the synthesis of the C13-C19 fragment is outlined. A boron-mediated glycolate aldol has been used to install the C16-C17 anti stereochemistry and a substrate-controlled reduction at C15 delivered the hydroxyl with high diastereoselectivity. Studies into the C¬17¬ methylation are also described. Chapter 4 describes the synthesis of one possible diastereomer of the C20-C25 fragment, as a template for the preparation of the other 7 possible diastereomers. The route therefore employs only catalyst based control methods to install the three stereocentres, utilising a Sharpless asymmetric epoxidation and Evans aldol to construct the stereotriad. The 22R, 23S, 24S diastereomer has been initially chosen to investigate the later chemistry. Chapter 5 contains discussion of the ongoing work investigating fragment union and formation of the macrocycle. A Heck coupling reaction has been employed to construct the C19-C20 bond and a Suzuki coupling reaction has been developed to facilitate the C12-C13 bond formation. These two cross couplings have delivered the C1 - C25 fragment, 360, the final compound reported in this thesis, which is three steps away from the completed macrocycle and six from compound 36. The experimental procedures and spectroscopic characterisation of the synthesised intermediates can be found in Chapter 6 and the Appendix.

Life, as we know it, has emerged from the association of simple building blocks (e.g. HCN, NH3, aldehydes, etc). The reactions required to form the complex subunits of life face a great entropic barrier due to the intermolecular nature of their reactivity. Intermolecular reactions are slow at low concentrations, and therefore, the assembly of complex subunits requires the presence of a concentration mechanism. Formaldehyde, which was present in concentrations as high as 0.02 M, may have been used as a concentration mechanism on early Earth. By tethering two molecules together, formaldehyde allows catalysis via temporary intramolecularity. Moreover, formaldehyde has been shown to act as a hydrolase / hydratase mimic, allowing important rate accelerations in hydration and hydrolysis reactions which are of fundamental importance to prebiotic chemistry. Herein, the efficiency of formaldehyde as a catalyst, operating via temporary intramolecularity is demonstrated for a hydroamination reaction that occurs in dilute aqueous conditions. First, using soluble N-methylallylamine and Nmethylhydroxylamine, formaldehyde allowed catalytic turnover at prebiotically relevant formaldehyde concentrations (0.02 M) for a model hydroamination reaction. The efficiency of formaldehyde was compared to other prebiotic aldehydes, demonstrating that although other prebiotic aldehydes are capable of inducing temporary intramolecularity, they were inferior.A second small molecule which may have played a role in the origin of life is D-glyceraldehyde. Since life’s molecules are homochiral, there is a need to explain how this homochirality arose. There have been many breakthroughs by the scientific community when it comes to addressing this challenge, however there is still no general consensus on the origins of homochirality from a prebiotic perspective. Herein, we demonstrate that D-glyceraldehyde is capable of templating a challenging intermolecular reaction while also transmitting some of its chirality to the product. Though the enantiomeric excess produced was generally low (usually around 20 %), there is a significance behind these results due to prebiotically relevant amplification procedures. Lastly, formaldehyde is examined as a possible desymmetrizing agent; coupled with Brønsted acids, the possibility of formaldehyde to induce desymmetrization of alpha-amino or alpha-hydroxy diesters to produce azlactones, and oxalactones, respectively will be established. Moreover, the use of a chiral Brønsted acid would introduce the ability to achieve this transformation in an enantioselective manner. The resulting azlactones / oxalactones are valuable for two reasons: 1) the lactones are present in bioactive molecules, and 2) the lactones can be hydrolyzed to produce chiral alpha-amino / alpha-hydroxy acids. Therefore, we began a systematic study of the conditions required to allow this transformation to occur. This study indicates that the desymmetrization of an alpha-amino diester is possible, producing moderate yields of the resulting azlactone. The desymmetrization of alpha-hydroxy diesters however proved more challenging, and no conversion was observed. Further investigation is required to the increase efficiency of the desymmetrizations, and experimentation with chiral Brønsted acids is required in order to discover enantioselective transformations.

In this thesis, the synthesis, reactivity and enantioselectivity of novel chiral Selectfluor Analogues were investigated. Chapter 1: Discussed is a general introduction to Selectfluor as an achiral electrophilic fluorinating reagent and its role as an oxidant in a wide variety of transformations and summarises the aims and objectives of the project. Chapter 2: The synthesis of chiral 2-monosubstituted, 2,3-disusbstituted and 2,5-disubstituted DABCO derivatives is described. We selected two strategies to prepare these chiral analogues of DABCO. Strategy A takes advantage of a large range of commercially available natural and unnatural amino acids. 2,3-Disubstituted DABCO motifs were prepared via a protocol of Sharpless in strategy B. Eleven chiral DABCO systems have been synthesized, six of which are novel compounds. Chapter 3 describes the synthesis of novel chiral non-racemic Selectfluor analogues using F₂. Mono-fluorinated chiral DABCOs were found to be unstable at low temperature, however, quaternized derivatives of these chiral reagents induced stability1. The fluorination proved challenging with chiral DABCO derivatives having sterically demanding substituents. Moreover, we have developed a practical and general process for the synthesis of novel chiral non-racemic Selectfluor using N-fluoropentachloropyridinium triflate 221. This methodology alleviates the need to handle F₂ gas. In Chapter 4: An investigation into how chiral Selectfluor analogues compare to N-F derived cinchona alkaloids in term of reactivity and enantioselectivity. The reactivity of the chiral Selectfluor analogues was challenged with both activated and less activated substrates. The novel chiral Selectfluor analogues showed superior reactivity than the cinchona alkaloids. Moderate to excellent yields of the desired products were obtained for all of the substrates studied.

The aim of this project was to utilize chiral cation-directed catalysis in the asymmetric synthesis of novel hererocycles. This goal was initially realized by the synthesis of azaindolines in high yields and enantioselectivities (Chapter 2). Extension of this methodology to substrates bearing two stereogenic centres was successful, although control over both diastereoselectivity and enantioselectivity in this process was modest. Finally the synthesis of heterocycles utilizing cation-directed rearrangement processes was examined, with proof of concept obtained for a novel asymmetric cyclization to form xanthenes.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.