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Density Functional Theory is used in order to shed light on the reaction mechanisms and the origins of stereoselectivity in enantioselective organocatalytic reactions. The reactions investigated are the dipeptide-catalyzed aldol reaction, the cinchona thiourea-catalyzed nitroaldol reaction and the prolinol derivative-catalyzed hydrophosphination reaction. We can justify the stereoselectivity in the reactions from the energies arising from different interactions in the transition states. The major contributions to the energy differences are found to be hydrogen bond-type attractions and steric repulsions. This knowledge will be useful in the design of improved catalysts as well as general understanding of the basis of selection in other reactions. / QC 20101111

There are immense efforts to install the trifluoromethyl group (CF3) into organic molecules since it significantly affects reactivity, as well as the biological and pharmaceutical properties of the molecule. The α-trifluoromethylacrylates are useful synthetic intermediates for the synthesis of trifluoromethyl-bearing nucleosides or peptides. However, methods to prepare such derivatives are scarce and suffer narrow substrate scope, lack of diastereoselectivity, use of costly reagents, and lack of user‐friendliness. Chapter 2 discusses the synthesis of α‐trifluoromethylacrylates from converting shelf-stable α‐trifluoroborylacrylates via a stereoretentive radical trifluoromethylation with inexpensive reagents NaSO2CF3 and TBHP with copper catalysis at room temperature. Under these conditions, a wide substrate scope afforded the (E)‐diastereomer exclusively in moderate to good yield. The reaction products' utility is demonstrated in synthesizing phenyl‐4H‐pyran, a potent and selective class of IKCa channel blockers. Branching out from metal-catalyzed reactions, Chapter 3 and 4 discusses metal-free organo-catalytic reactions which are more economical and greener. Boron-containing compounds are important in organic chemistry due to the different transformations that can be performed to afford useful synthetic intermediates and pharmaceuticals. Chapter 3 elaborates on the Borylation of 1,3-butadiynes, which are molecules that are widely used to synthesize biologically active molecules, polymers, and supramolecular tools under phosphine-catalyzed conditions. The reaction proceeds with both regio- and stereo-selectivity, and the boryl group is installed on the beta carbon to the alkyne in a trans fashion as established from 2D NMR and X-ray crystallography. The reaction products are converted into useful intermediates under Suzuki Miyuara, protodeborylation, etc. 31P NMR tudies were conducted to understand the mechanism of the reaction, which is supported by the DFT calculations revealing that phosphine attack is the most crucial step. A similar strategy was utilized with pinacol borane and tri-n-butyl phosphine catalyst to achieve borylation on ynamides (Chapter 4). A wide variety of ynamides underwent hydroboration to install the boron group in a regio- and stereoselective fashion. Under radical trifluoromethylating conditions, the boryl moeity was converted into the trifluoromethyl group to afford β-CF3 enamides. 31P NMR studies were conducted to elucidate the mechanism. Finally, chapter 5 provides insight into the synthesis of 1,2,4-Oxadiazoles which are privileged scaffolds in medicinal chemistry. The developed reaction occurs under metal-free conditions using sodium carbonate to couple N-hydroxylbenzenecarbonimodyl chlorides with nitriles. / Doctor of Philosophy / Installing fluorine in organic molecules significantly improves their pharmaceutical properties and the trifluoromethyl (CF3) group is one such group. Chapter 2 describes a simple, cost-effective method to synthesize trifluoromethylated compounds with readily available reagents under copper-catalyzed conditions, whereas in Chapters 3 and 4, a metal-free method is discussed. In comparison with metal catalysts, organo catalysts are less toxic, readily available, avoid contamination, and are more economic. Boron is used for different transformations in organic chemistry and for making medicinally relevant molecules. An organo-catalytic method to install boron on various substrates and potential applications of such molecules as synthetic intermediates are discussed. 1,2,4-Oxadizoles are molecules that are considered privileged scaffolds imparting pharmaceutical properties. Finally, in Chapter 5, a procedure to synthesize 1,2,4-Oxadiazoles under mild reaction conditions and readily available reagents are discussed.

This thesis details the studies towards the total synthesis of the calyciphylline A-type Daphniphyllum alkaloids, with a particular focus on daphniyunnine D (23). Chapter 1 introduces these biologically and synthetically interesting polycyclic natural products and describes our designed approach towards their synthesis. Separate studies targeting the construction of two tricyclic ring systems have been developed. These provide rapid entry to synthetically versatile intermediates, allowing for the potential synthesis of numerous members of the alkaloid family. Chapter 2 describes the first study which focuses on the construction of the main tricyclic [6‒5‒7] ACD core 172 via a proton transfer/IMDAF reaction cascade as the main step. Large scale synthesis of the precursor to this cascade 164 has allowed for the successful investigation of an asymmetric variant giving rise to an enantioenriched adduct 104. Chapter 3 describes a novel design for the construction of the [7‒5‒5] DEF tricycle common to 100+ Daphniphyllum alkaloids. An IMPKR, double-bond migration, allylic oxygenation protocol was first validated on a model system and later applied in combination with the synthetic route developed in chapter 2 to achieve the construction of the [6‒5‒7‒5‒5] ACDEF pentacycle 249. Chapter 4 focuses on the construction of the piperidine ring B via an intramolecular gold-catalysed 6-exo-trig hydroalkylation. During the development of the route to daphniyunnine D, various intermediates were afforded which were further elaborated to provide appropriate cyclisation substrates for this study. Their synthesis combined with proof of principle experiments for the desired cyclisation conclude this dissertation work.

Ion-binding organocatalysis is an emerging field that has the potential to control the stereochemical outcome of any transformation that goes via charged intermediates. The aim of this project was to explore how this concept could be applied to an asymmetric allylation reaction. Chapter 2 of this thesis discusses anion-binding catalysis and investigates a chiral cooperative thiourea catalyst that could bind to fluoride to control allylation using an allylsilane. Optimization using a non-chiral thiourea (Schreiner’s catalyst) demonstrated that the reaction proceeded in high yield with TBAT onto an N-benzoylhydrazone. A chiral cooperative thiourea catalyst library was then synthesized but unfortunately, although the allylation using these catalysts proceeded in excellent yield, the product was isolated as the racemate (Scheme 1). Scheme 1: Anion-binding catalysis gave allylated products in high yields but gave no stereocontrol. Chapter 3 examines a chiral quaternary ammonium fluoride as an example of chiral cation-directed catalysis. We hypothesized that an allylsilane activated by fluoride would generate an allyl anion species that would associate with the chiral quaternary ammonium cation through electrostatic interactions. Extensive optimization found that the allylation reaction proceeded in good yield in chloroform at reflux with N-benzoylhydrazones. Different fluoride catalysts were prepared using an ion-exchange resin, and cinchonidine-derived catalysts performed the best. This methodology was extended to a phase-transfer catalyzed process, where solid cesium fluoride exchanged with chloride in situ, removing the need to synthesize and isolate ammonium fluoride catalysts (Scheme 2). Scheme 2: Cation-directed asymmetric allylation. In Chapter 4 cation-directed asymmetric catalysis was extended to an intramolecular allylation reaction. Substrate synthesis was attempted by cross metathesis but the reaction was capricious and yields were low. Intramolecular allylation with these materials gave promising results (Scheme 3) but a lack of material prevented optimization. Scheme 3: Intramolecular allylation results.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

Bifunctional iminophosphoranes, containing a triaryl-substituted iminophosphorane and bis(3,5- trifluoromethyl)phenyl thiourea on a single enantiomer scaffold are novel asymmetric superbase organocatalysts reported by the Dixon group in 2014. This thesis describes our efforts to expand their scope and utility in a variety of challenging chemical transformations. Chapter 2 describes the development and application of immobilised bifunctional iminophosphorane organocatalysts. We have successfully immobilised bifunctional iminophosphoranes on a crosslinked polystyrene support and applied this sold-supported catalyst to three challenging asymmetric reactions; namely the nitro-Mannich reaction of phosphinoyl ketimines and the conjugate addition of alkylmalonates and N,N-dimethyl β-keto amides to nitrostyrene. Very good yields, enantio- and diasteroselectivities were obtained in all cases. We have also demonstrated their use in a range of conjugate additions of cyclic 1,3-dicarbonyl compounds to nitroalkenes, which suffered from very slow reaction rates under tertiary amine-based bifunctional catalysis. In all cases, the immobilised bifunctional iminophosphoranes performed very well in comparison to their homogeneous counterparts. We have also demonstrated catalyst recycling over 10 cycles and application in a continuous flow system with a productivity of 7.20 mmol _producth^-1g_catalyst^-1. to the ring-opening polymerisation (ROP) of cyclic esters. We have demonstrated the performance of bifunctional iminophosphorane organocatalysts in the ROP of L-lactide (LA), δ-valerolactone (VL) and ε-caprolactone (CL). The polymerisation of LA and VL proceeded rapidly and was well controlled, while only short lengths (> 100 DP) of poly(CL) could be prepared in a controlled fashion due to hypothesised competing initiation from the catalyst. We have shown that the polymerisation of LA using our catalyst may be considered a living polymerisation. Di-block co-polymers could also be successfully prepared via sequential monomer addition or through the use of macroinitiators. We then investigated the roles of the iminophosphorane and the thiourea component of the catalyst.

This diploma thesis deals with the scope of organocatalytic concept for the preparation of enantiomerically pure organic compounds, containing fluorine atom. Our attention was focused on the use of easily available α,β-unsaturated aldehydes and ketones as starting materials and commercially available secondary amines as catalysts. The first part of the work is dedicated to the enantioselective cyclization reaction of hydrazone (24) with cyclohex-2-enone (25). The second part describes a study of enantioselective nucleophilic addition of diethyl 2-fluoromalonate (31a) to α,β-unsaturated aldehydes (30) via enamine activation.

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