The development of new aza-bicyclic structures with potential applications as ligands synthesised via an aza-Diels-Alder cycloaddition has been studied. The studies are concerning the i) development of large scale aza-Diels-Alder reaction, ii) development of a fast and simple route to bicyclic diamine ligands, iii) development of new aza-Diels-Alder adducts from different dienes, iv) development and application of bicyclic N,P ligands for catalytic Michael additions and v) development of robotized asymmetric transfer hydrogenation reactions. i) Development of large-scale aza-Diels-Alder reaction giving up to 110 g pure product, in ordinary laboratory equipment without the need of any flash chromatography. ii) Development of a new synthetic route to bicyclic diamine ligands highly useful for asymmetric rearrangement of olefin oxides to allylic alcohols and thereby shortening the ligand synthesis dramatically and moreover providing with a faster access to those ligands. iii) Expanding the scope of the aza-Diels-Alder reaction by the use of spirodienes and anthracene as dienes. iv) Development and application of a new bidentate ligands for catalytic Michael addition to cyclic enones using 5 mol % ligand giving the product in 71 % ee. v) Utilisation of Chemspeed ASW 2000 in catalytic transfer hydrogenation and solving of problems regarding use of highly air sensitive reactions in an automated environment.

The work described in this thesis is focused on the development of new bidentate iridium complexes and their applications in the asymmetric reduction of olefins, ketones and imines. Three new types of iridium complexes were synthesized, which included pyridine derived chiral N,P-iridium complexes, achiral NHC complexes and chiral NHC-phosphine complexes. A study of their catalytic applications demonstrated a high efficiency of the N,P-iridium complexes for asymmetric hydrogenation of olefins, with good enantioselectivity. The carbene complexes were found to be very efficient hydrogen transfer mediators capable of abstracting hydrogen from alcohols and subsequently transfer it to other unsaturated bonds. This hydrogen transferring property of the carbene complexes was used in the development of C–C and C–N bond formation reactions via the hydrogen borrowing process. The complexes displayed high catalytic reactivity using 0.5–1.0 mol% of the catalyst and mild reaction conditions. Finally chiral carbene complexes were found to be activated by hydrogen gas. Their corresponding iridium hydride species were able to reduce ketones and imines with high efficiency and enantioselectivity without any additives, base or acid. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 5: Submitted. Paper 6: Manuscript.</p><p> </p>

A detailed mechanistic investigation of the previously reported ruthenium pseudo-dipeptide-catalyzed asymmetric transfer hydrogenation (ATH) of aromatic ketones was performed. It was found that the addition of alkali metals has a large influence on both the reaction rate and the selectivity, and that the rate of the reaction was substantially increased when THF was used as a co-solvent. A novel bimetallic mechanism for the ruthenium pseudo-dipeptide-catalyzed asymmetric reduction of prochiral ketones was proposed. There is a demand for a larger substrate scope in the ATH reaction, and heteroaromatic ketones are traditionally more challenging substrates. Normally a catalyst is developed for one benchmark substrate, and a substrate screen is carried out with the best performing catalyst. There is a high probability that for different substrates, another catalyst could outperform the one used. To circumvent this issue, a multiple screen was executed, employing a variety of ligands from different families within our group’s ligand library, and different heteroaromatic ketones to fine-tune and to find the optimum catalyst depending on the substrate. The acquired information was used in the formal total syntheses of (R)-fluoxetine and (S)-duloxetine, where the key reduction step was performed with high enantioselectivities and high yield, in each case. Furthermore, a new iron-N-heterocyclic carbene (NHC)-catalyzed hydrosilylation (HS) protocol was developed. An active catalyst was formed in situ from readily available imidazolium salts together with an iron source, and the inexpensive and benign polymethylhydrosiloxane (PMHS) was used as hydride donor. A set of sterically less demanding, potentially bidentate NHC precursors was prepared. The effect proved to be remarkable, and an unprecedented activity was observed when combining them with iron. The same system was also explored in the reduction of amides to amines with satisfactory results. / <p>At the time of doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.</p>

In this thesis a methodology to synthesize anti-β-hydroxy-α-amino esters possessing olefins has been investigated. The developed procedures originate from two already established procedures in which α-amido-β-keto esters, which do not contain olefins, has been stereoselectively reduced to the corresponding anti-β-hydroxy-α-amino alcohols via asymmetric transfer hydrogenation coupled with dynamic kinetic resolution. Both established methods, one solvent free and one emulsion procedure, have been investigated on the expanded substrate scoop. Four different α-amido-β-keto ester containing olefins were tested and it was found that the ketones were reduced to desired anti-β-hydroxy-α-amino esters in both procedures, but also side products were formed where the olefins were reduced. The ratio of the different products was dependent on the structure of the starting α-amido-β-keto ester, ligand used on the catalyst and reaction conditions such as number of equivalents of base and reaction temperature. The diastereoselectivity for the desired products was in favor of the anti stereoisomer, however, the dr was worse than in the established procedures. The usefulness of this methodology was then demonstrated by a formal total synthesis of Sphingosine.

Increasing energy demand and various problems associated with fossil fuels such as environmental pollution, global warming and diminishing petroleum reserves have greatly stimulated production of fuels and chemicals from renewable sources. Lignocellulosic biomass has been considered as one of the potential sources for a variety of fuels and industrial chemicals. 5-Hydroxymethylfurfural (HMF) has been identified as an excellent platform molecule because it is a flexible intermediate for the synthesis of bio-renewable fuels and materials. HMF can be easily obtained from acid-catalyzed hydration of biomass-derived carbohydrates (hexoses) in various media. HMF can be converted to energy products such as 2,5-bis(alkoxymethyl)furans (BAMFs), monomers for high-value polymers such as 2,5-bis(hydroxymethyl)furan (BHMF), and valuable intermediates for fine chemicals. Recently, magnetic nanoparticle based catalysts attracted more attention due to their good stability and easy separation from the reaction mixture by a permanent magnet. This unique magnetic separation property makes MNPs more effective than conventional filtration or centrifugation as it prevents loss of the catalyst. This dissertation work focuses on, firstly, studying the effectiveness of silica coated magnetite (Fe3O4) nanoparticles MNPs supported with sulfonic acid groups (Fe3O4@SiO2-SO3H) on the dehydration of glucose to HMF. Secondly, preparing a cost-effective catalytic transfer hydrogenation system for the selective transformation of HMF into BHMF via Meerwein-Ponndorf-Verley (MPV) reaction over the copper iron magnetic catalyst supported on activated carbon in ethanol solvent with the absence of molecular hydrogen. Thirdly, producing alkoxymethylfurans (AMFs) which are considered a potential biofuels by using two-step sequential reactions with cheap heterogeneous zinc-iron oxides magnetic nanocatalyst for the hydrogenation of HMF to furfuryl alcohols in various alcohols solvents in the absence of molecular hydrogen followed by solid Brønsted acid catalyst for the etherification reaction of furfuryl alcohol derivatives. All prepared heterogeneous catalysts were characterized by FTIR, XRD, H2-TPR, XPS, ICP-OES, HRTEM-EDX, and N2 adsorption-desorption isothermal analyses (BET and BJH) and were tested for recyclability. The chemical products were identified by high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), and products quantities were calculated by using calibration curves of chemical standards. Various reaction conditions such as reaction temperature, reaction time, catalyst amount, and alcohol type were optimized.

<p>This thesis describes the synthesis and application of new chiral bicyclic ligands and their application in asymmetric catalysis. The studies involved: [i] The development of novel chiral bicyclic amino sulfur ligands and their use in transfer hydrogenation. [ii] The development of the kinetic resolution of racemic epoxide through the use of chiral lithium amides. [iii] The synthesis and application of chiral bicyclic amine in the organocatalysed epoxidation of alkenes. [iv] Development and application of new chiral diamine ligands in the rearrangement of epoxides into allylic alcohols.</p><p>[i] The preparation of two-series of amino thiol ligands based on the structure of camphor is described, together with their application in the iridium-catalysed asymmetric transfer hydrogenation of acetophenone using isopropanol as the hydrogen source. Excellent activity and good enantioselectivity have been achieved using 2 mol% of chiral ligand in combination with [IrCl(COD)]2.</p><p>[ii] The chiral diamines (1S,3R,4R)-3-(pyrrolidine-1-ylmethyl)-2-aza-bicyclo[2.2.1]heptane and its (2R,5R)-dimethylpyrrolidine derivative were applied to the kinetic resolution of a variety of racemic 5-7 membered cycloalkene oxides with lithium diisopropylamide (LDA) as the bulk base. Using 5 mol% of the chiral diamines, both unreacted epoxides and allylic alcohols could be produced in enantiomeric excess up to 99%.</p><p>[iii] The synthesis of chiral bicyclic amines and their use in the organocatalysed epoxidation of alkene has been described. Using a substoichiometric amount of the chiral amines and aldehydes as ligands precursors, with Oxone® as oxidant, a good activity but moderate enantioselectivity was observed for the epoxidation of trans-stilbene. </p><p>[iv] The preparation of 6-substituted-7-bromo-aza-bicyclo[2.2.1]heptanes via nucleophilic addition of organocopper reagents to 3-bromo-1-azoniatricyclo[2.2.1.0]heptyle bromide has been described. These compounds have been utilised as chiral building blocks in the preparation of novel chiral diamine ligands, which have been successfully applied to the catalysed asymmetric rearrangement of epoxide into the corresponding allylic alcohol.</p>

<p>The synthesis of 2-aza-norborane derivatives is presented. The use of these compounds in preparation of Ir catalysts for asymmetric hydrogenations is described. The evaluation and optimization of the catalysts as well as the mechanistic aspects of the catalytic process are discussed.</p><p>The use of non-activated iminodieniphiles in stereoselective aza-Diels-Alder reaction has expanded the scope of the reaction and provided a convenient root for preparation of 2-aza-norboranes, analogues of which were developed into novel bicyclic 2-aza-norbornyl-oxazoline ligands for Ir-catalyzed asymmetric transfer hydrogenations. Using ths Ir complexes acetophenone was hydrogenated in 79% ee.</p><p>2-Aza-norbornyl-oxazolines were also developed into novel N,P-ligands. Resulting phosphine-oxazolines were evaluated in Ir-catalyzed asymmetric hydrogenation of structurally diverse imines and olefins.</p><p>Optimization of ligands was performed through: 1) Alteration of the stereoconfiguration at the 5’-position as well as variation of the size and geometry of the substituents at this position; 2) Screening through various phosphine substituents of the ligand. Both directions of optimization reflect on the influence of the ligands’ sterik bulk on stereoselectivity of catalytic process. High performance catalysts were developed for both transformations allowing asymmetric hydrogenation of imines with 92% ee and asymmetric hydrogenation of olefins with 99% ee.</p><p>Possible mechanisms for these transformations were suggested based on computational studies. Selectivity model for rationalization of results of Ir-catalyzed olefin hydrogenation also was designed.</p>

This thesis describes the synthesis and application of new chiral bicyclic ligands and their application in asymmetric catalysis. The studies involved: [i] The development of novel chiral bicyclic amino sulfur ligands and their use in transfer hydrogenation. [ii] The development of the kinetic resolution of racemic epoxide through the use of chiral lithium amides. [iii] The synthesis and application of chiral bicyclic amine in the organocatalysed epoxidation of alkenes. [iv] Development and application of new chiral diamine ligands in the rearrangement of epoxides into allylic alcohols. [i] The preparation of two-series of amino thiol ligands based on the structure of camphor is described, together with their application in the iridium-catalysed asymmetric transfer hydrogenation of acetophenone using isopropanol as the hydrogen source. Excellent activity and good enantioselectivity have been achieved using 2 mol% of chiral ligand in combination with [IrCl(COD)]2. [ii] The chiral diamines (1S,3R,4R)-3-(pyrrolidine-1-ylmethyl)-2-aza-bicyclo[2.2.1]heptane and its (2R,5R)-dimethylpyrrolidine derivative were applied to the kinetic resolution of a variety of racemic 5-7 membered cycloalkene oxides with lithium diisopropylamide (LDA) as the bulk base. Using 5 mol% of the chiral diamines, both unreacted epoxides and allylic alcohols could be produced in enantiomeric excess up to 99%. [iii] The synthesis of chiral bicyclic amines and their use in the organocatalysed epoxidation of alkene has been described. Using a substoichiometric amount of the chiral amines and aldehydes as ligands precursors, with Oxone® as oxidant, a good activity but moderate enantioselectivity was observed for the epoxidation of trans-stilbene. [iv] The preparation of 6-substituted-7-bromo-aza-bicyclo[2.2.1]heptanes via nucleophilic addition of organocopper reagents to 3-bromo-1-azoniatricyclo[2.2.1.0]heptyle bromide has been described. These compounds have been utilised as chiral building blocks in the preparation of novel chiral diamine ligands, which have been successfully applied to the catalysed asymmetric rearrangement of epoxide into the corresponding allylic alcohol.

The synthesis of 2-aza-norborane derivatives is presented. The use of these compounds in preparation of Ir catalysts for asymmetric hydrogenations is described. The evaluation and optimization of the catalysts as well as the mechanistic aspects of the catalytic process are discussed. The use of non-activated iminodieniphiles in stereoselective aza-Diels-Alder reaction has expanded the scope of the reaction and provided a convenient root for preparation of 2-aza-norboranes, analogues of which were developed into novel bicyclic 2-aza-norbornyl-oxazoline ligands for Ir-catalyzed asymmetric transfer hydrogenations. Using ths Ir complexes acetophenone was hydrogenated in 79% ee. 2-Aza-norbornyl-oxazolines were also developed into novel N,P-ligands. Resulting phosphine-oxazolines were evaluated in Ir-catalyzed asymmetric hydrogenation of structurally diverse imines and olefins. Optimization of ligands was performed through: 1) Alteration of the stereoconfiguration at the 5’-position as well as variation of the size and geometry of the substituents at this position; 2) Screening through various phosphine substituents of the ligand. Both directions of optimization reflect on the influence of the ligands’ sterik bulk on stereoselectivity of catalytic process. High performance catalysts were developed for both transformations allowing asymmetric hydrogenation of imines with 92% ee and asymmetric hydrogenation of olefins with 99% ee. Possible mechanisms for these transformations were suggested based on computational studies. Selectivity model for rationalization of results of Ir-catalyzed olefin hydrogenation also was designed.

The development and application of unnatural amino alcohols,prepared via hetero-Diels-Alder reactions,in synthesis and catalysis is described.The studies are concerned with the [i]scope of the hetero-Diels-Alder reaction and preparation of important intermediates in the synthesis of antiviral agents,[ii ]application of amino alcohols in the ruthenium transfer hydrogenation of ketones,[iii ]use of similar precursors in the in situ generation of oxazaborolidines for reduction of ketones,and [iv] development and application of new chiral auxiliaries for dialkylzinc additions to activated imines, respectively. [i ]The use of chiral exo -2-azanorbornyl-3-carboxylates in the preparation of enantiopure cyclopentyl-amines is described.At the same time the scope of the hetero-Diels-Alder reaction,used in their preparation,is extended by manipulations of the dienophiles. [ii ]Application of 2-azanorbornyl-3-methanol as a very efficient ligand in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones.This ligand (2 mol%)in combination with [RuCl2(p -cymene)]2 (0.25 mol%)gave rise to a very fast reaction (1.5 h)leading to the reduced products in excellent yields and enantioselectivities (up to 97%ee ). [iii ]Preparation of α-disubstituded 2-azanorbornyl-3-methanols,in situ generation of the corresponding oxazaborolidines,and use of the latter in reduction of aromatic ketones.Concentration, solvent,and temperature effects on the reaction outcome are described. [iv ]Development of two generations of chiral auxiliaries for the addition of dialkylzinc reagents to N - (diphenylphosphinoyl)imines.Studies using density functional computations allowed the rationalisation of the reaction mechanism and the development of a second generation of ligands that improved the previously reported results.Up to 98%ee could be obtained with these new ligands. Solvent effects on the outcome of the reaction and extension of the work to a larger variety of N - (diphenylphosphinoyl)imines are described.