Dynamic kinetic resolution (DKR) is a powerful method for obtaining compounds with high optical purity. The process relies on the combination of a kinetic resolution with an in situ racemization. In this thesis, a combination of an immobilized hydrolase and a transition metal-based racemization catalyst was employed in DKR to transform racemic alcohols and amines into enantioenriched esters and amides, respectively. In the first part the DKR of 1,2-amino alcohols with different rings sizes and N-protecting groups is described. We showed that the immobilization method used to support the lipase strongly influenced the stereoselectivity of the reaction. The second part deals with the DKR of C3-functionalized cyclic allylic alcohols affording the corresponding allylic esters in high yields and high ee’s. The protocol was also extended to include carbohydrate derivatives, leading to inversion of a hydroxyl substituted chiral center on the carbohydrate. The third part focuses on an improved method for obtaining benzylic primary amines. By using a novel, recyclable catalyst composed of Pd nanoparticles on amino-functionalized mesocellular foam, DKR could be performed at 50 °C. Moreover, Lipase PS was for the first time employed in the DKR of amines. In the fourth part DKR was applied in the total synthesis of Duloxetine, a compound used in the treatment of major depressive disorder. By performing a six-step synthesis, utilizing DKR in the enantiodetermining step, Duloxetine could be isolated in an overall yield of 37% and an ee &gt;96%. In the final part we investigated how the enantioselectivty of reactions catalyzed by Candida Antarctica lipase B for δ-substituted alkan-2-ols are influenced by water. The results showed that the enzyme displays much higher enantioselectivity in water than in anhydrous toluene. The effect was rationalized by the creation of a water mediated hydrogen bond in the active site that helps the enzyme form enantiodiscriminating binding modes. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.</p>

The work described in this thesis is focused on exploring the efficacy of iridium-catalysed asymmetric hydrogenation of precursors to chiral alcohols and chiral cyclohexanes. A range of allylic alcohols including γ,γ-dialkyl allylic alcohols and (Z)-allylic alcohols were prepared and evaluated in the asymmetric hydrogenation using iridium catalysts resulting in chiral alcohols in high yields and excellent enantioselectivity. This methodology was applied in the formal synthesis of Aliskiren, an efficient renin inhibitor drug, using the asymmetric hydrogenation of an allylic alcohol as a key-step. Another project concerned the dynamic kinetic resolution of racemic secondary allylic alcohols using Ir-N,P catalysts under hydrogenation conditions. A range of secondary allylic alcohols and protected alcohols were evaluated in the asymmetric hydrogenation via dynamic kinetic resolution using Ir-N,P catalysts. The corresponding chiral saturated alcohols were formed in good yield with excellent diastereoselectivites (up to 95/5) and enantioselectivities (&gt;99% ee). The last part of this thesis is directed towards the development of highly regio- and enantioselective asymmetric hydrogenation of 1,4-cyclohexadienes and its application in the preparation of useful chiral cyclohexenone intermediates. Non-functionalised, functionalised and heterocycle-containing cyclohexadienes were evaluated. Good yield of regioselectively mono-hydrogenated silyl protected enol ethers were obtained in most cases with excellent enantioselectivity. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 5: Manuscript.</p>

Enzymes are attractive catalysts in organic synthesis since they are efficient, selective and environmentally friendly. A large number of enzyme-catalyzed transformations have been described in the literature. If no natural enzyme can carry out a desirable reaction, one possibility is to modify an existing enzyme by protein engineering and thereby obtain a catalyst with the desired properties. In this thesis, the development of enantioselective enzymes and their use in synthetic applications is described.  In the first part of this thesis, enantioselective variants of Candida antarctica lipase A (CALA) towards α-substituted p-nitrophenyl esters were developed by directed evolution. A highly selective variant of CALA towards p-nitrophenyl 2-phenylpropanoate was developed by pairwise randomization of amino acid residues close to the active site. The E value of this variant was 276 compared to 3 for the wild type. An approach where nine residues were altered simultaneously was used to discover another highly enantioselective CALA variant (E = 100) towards an ibuprofen ester. The sterical demands of this substrate made it necessary to vary several residues at the same time in order to reach a variant with improved properties. In the second part of the thesis, a designed variant of Candida antarctica lipase B (CALB) was employed in kinetic resolution (KR) and dynamic kinetic resolution (DKR) of secondary alcohols. The designed CALB variant (W104A) accepts larger substrates compared to the wild type, and by the application of CALB W104A, the scope of these resolutions was extended. First, a DKR of phenylalkanols was developed using CALB W104A. An enzymatic resolution was combined with in situ racemization of the substrate, to yield the products in up to 97% ee. Secondly, the KR of diarylmethanols with CALB W104A was developed. By the use of diarylmethanols with two different aryl groups, highly enantioselective transformations were achieved. / At the time of the doctoral defense, the following paper was unpublished and had a status as follows:<strong>  </strong>Paper 5: Submitted.

The main focus of this thesis lies on transition metal-catalyzed hydrogen transfer reactions. In the first part of the thesis, the mechanism for racemization of sec-alcohols with a ruthenium complex, Ru(CO)2Cl(η5-C5Ph5) was studied. The reaction between 5-hexen-2-ol and Ru(CO)2(Ot-Bu)(η5-C5Ph5) was studied with the aim to elucidate the origin of the slow racemization observed for this sec-alcohol. Two diastereomers of an alkoxycarbonyl complex, which has the double bond coordinated to ruthenium, were characterized by NMR and in situ FT-IR spectroscopy. The observed inhibition of the rate of racemization for substrates with double bonds provided further confirmation of the importance of a free coordination site on ruthenium for β-hydride elimination. Furthermore, we observed that CO exchange, monitored by 13C NMR using 13CO, occurs with both the precatalyst, Ru(CO)2Cl(η5-C5Ph5), and the active catalytic intermediate, Ru(CO)2(Ot-Bu)(η5-C5Ph5). It was also found that added CO has an inhibitory effect on the rate of racemization of (S)-1-phenylethanol. Both these observations provide strong support for reversible CO dissociation as a key step in the racemization mechanism. In the second part of this thesis, Ru(CO)2Cl(η5-C5Ph5) was combined with an enzymatic resolution catalyzed by a lipase, leading to several efficient dynamic kinetic resolutions (DKR). DKR of exocyclic allylic alcohols afforded the corresponding acetates in high yields and with excellent enantiomeric excess (ee). The products were utilized as synthetic precursors for α-substituted ketones and lactones. DKR of a wide range of homoallylic alcohols afforded the products in good to high yields and with high ee. The homoallylic acetates were transformed into 5,6-dihydropyran-2-ones in a short reaction sequence. Furthermore, DKR of a wide range of aromatic β-chloroalcohols afforded the products in high yields and with excellent ee. The β-chloro acetates were further transformed into chiral epoxides. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 5: Mansucript.</p>

In the emerging aield of molecular machines, a molecular ratchet is a chemical system that allows the positional displacement of a submolecular component of be captured and directionally released. In information ratchets, the track over which a Brownian particle is to be transported is able to respond to the particle’s position. By raising energetic barriers to translation selectively behind the particle, it is possible to move the particle in a forward direction. This Thesis describes the development of a series of chemically-­‐driven information ratchets based on rotaxane architectures. Acylation of the rotaxane thread presents an impassible kinetic barrier to macrocycle shuttling. The incorporation of chiral centres into the thread allows the macrocycle’s position to have an effect on the kinetics of acylation in a chiral environment, with the result that the macrocycle is transported by successive acylation reactions in a direction speciaied by the handedness of a chiral. In Chapter One the physical principles of molecular motors are examined. It is shown that molecular motors are a subset of the much broader class of “triangular” reactions investigated by Onsager in 1931. Progress in the exciting aield of artiaicial chemical ratchets and motors is reviewed, and the deep connections between molecular motors and the cyclic reaction networks postulated to explain the origin of biological homochirality are explored. Chapter Two describes the synthesis and operation of a three-­‐compartment rotaxane information ratchet in which the macrocycle can be transported along a thread in either direction depending on the handedness of a chiral catalyst. Internal mechanisms of operation are elucidated by treating the system as a hidden Markov process. Chapter Three describes the synthesis and operation of a second-­‐generation three-­‐compartment information ratchet. A comparison between this system and that of the previous chapter sheds light on the complicated trade-­‐offs between kinetics and thermodynamics when these molecular ratchets are operated. In Chapter Four the ongoing efforts to construct extended information ratchets, incorporating many repeat units, are described. The synthesis of a aive-­‐ compartment information ratchet proved unexpectedly difaicult owing to problems of solubility. A four-­‐compartment rotaxane was easier to synthesise. Preliminary aindings suggest that an information ratchet mechanism is operating in this four-­‐compartment system.

This  thesis  is  divided  into  four  parts,  all  centered  around  Constitutional Dynamic  Chemistry  (CDC)  and  Dynamic  Kinetic  Resolution  (DKR)  using biocatalysts for selective transformations, and their applications in screening of bioactive compounds, organic synthesis, and enzyme classification.    In  part  one,  an  introduction  to  CDC  and  DKR  is  presented,  illustrating  the basic  concepts,  practical  considerations  and  potential  applications  of  such dynamic systems, thus providing the background information for the studies in the following chapters.   In part two, Dynamic Systemic Resolution (DSR), a concept based on CDC is exemplified.  With  enzyme-catalyzed  transformations  as  external  selection pressure,  optimal  structures  can  be  selected  and  amplified  from  the  system. This  concept  is  expanded  to  various  types  of  dynamic  systems  containing single, double cascade/parallel, and multiple reversible reactions. In addition, the  substrate  selectivity  and  catalytic  promiscuity  of  target  enzymes  are  also investigated.   In   part   three,   DKR   protocols   using   reversible   reactions   for   substrate racemizations  are  illustrated.  Biocatalysts  are  here  employed  for  asymmetric transformations,  resulting  in  efficient  synthetic  pathways  for  enantioenriched organic compounds.   Part  four  demonstrates  two  unique  applications  of  CDC:  one  resulting  in enzyme  classification  by  use  of  pattern  recognition  methodology;  the  other involving  enzyme  self-inhibition  through  in  situ  transformation  of  stealth inhibitors employing the catalytic activity of the target enzyme. / <p>QC 20130614</p>

The thiopyran route to polypropionates is an attractive strategy that involves a stepwise iterative aldol homologation of tetrahydro-4H-thiopyran-4-one (I) with thiopyran aldehyde (II) followed by desulfurization to rapidly assemble stereochemically complex polypropionate synthons. <p>In chapter 1, the thesis is summarized in the context of relevant background research including; a) the basic principle of the thiopyran route; b) dynamic kinetic resolution of -substituted aldehydes; c) previous syntheses of serricornin; iv) previous syntheses of membrenones.<p>In chapter 2, proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various achiral aldehydes were studied. The results provided insights on the behaviour and stereoselectivity profile of thiopyranone (a crucial starting block in the thiopyran design) in the proline-catalyzed aldol reaction.<p>In chapter 3, inspired by the results of the aldol reaction of ketone (I) with achiral aldehydes, we next investigated the proline-catalyzed asymmetric aldol reactions of (I) with racemic thiopyran aldehyde (II) as a strategy to rapidly prepare enantiomerically pure tetrapropionate synthons without any requirement of enantioenriched aldehyde. The reaction occurred with high enantiotopic group selectivity and dynamic kinetic resolution.<p>In chapter 4, a detailed study to ascertain the scope and limitations of the design strategy described in chapter 3 was extended towards other catalysts, aldehydes and ketones. <p>Finally, applications of the above mentioned strategy towards the synthesis of serricornin and membrenones A and B are elaborated in chapters 5 and 6 respectively.

The thiopyran route to polypropionates is an attractive strategy that involves a stepwise iterative aldol homologation of tetrahydro-4H-thiopyran-4-one (I) with thiopyran aldehyde (II) followed by desulfurization to rapidly assemble stereochemically complex polypropionate synthons. <p>In chapter 1, the thesis is summarized in the context of relevant background research including; a) the basic principle of the thiopyran route; b) dynamic kinetic resolution of -substituted aldehydes; c) previous syntheses of serricornin; iv) previous syntheses of membrenones.<p>In chapter 2, proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various achiral aldehydes were studied. The results provided insights on the behaviour and stereoselectivity profile of thiopyranone (a crucial starting block in the thiopyran design) in the proline-catalyzed aldol reaction.<p>In chapter 3, inspired by the results of the aldol reaction of ketone (I) with achiral aldehydes, we next investigated the proline-catalyzed asymmetric aldol reactions of (I) with racemic thiopyran aldehyde (II) as a strategy to rapidly prepare enantiomerically pure tetrapropionate synthons without any requirement of enantioenriched aldehyde. The reaction occurred with high enantiotopic group selectivity and dynamic kinetic resolution.<p>In chapter 4, a detailed study to ascertain the scope and limitations of the design strategy described in chapter 3 was extended towards other catalysts, aldehydes and ketones. <p>Finally, applications of the above mentioned strategy towards the synthesis of serricornin and membrenones A and B are elaborated in chapters 5 and 6 respectively.

Ce mémoire traite de l’utilisation d’allylmétaux chiraux, allylalanes et allylzincs, en synthèse asymétrique. Des stratégies adaptées à la stabilité configurationnelle intrinsèque de ces deux espèces ont été développées et appliquées à la synthèse d'alcools et d'amines homoallyliques énantioenrichis. La première partie de ce manuscrit est consacrée à la génération de cycloalkylèn-1-ylzincs à partir des alanes correspondants via une séquence hydroaluminationtitanocatalysée de diènes conjugués/transmétallation. Ces allylzincs, engagés dans l’allylmétallation d'imines non racémiques, conduisent aux amines homoallyliques correspondantes avec une bonne diastéréosélectivité selon un processus de résolution cinétique dynamique. La seconde partie vise à étudier l'influence des co-produits de transmétallation sur le cours stéréochimique de la réaction d'allylation d'imines. L'utilisation alternative d'allylzirconiums, qui libère un acide de Lewis inerte, se révèle bénéfique pour la stéréosélectivité de la réaction d’allylation d’imines. Le dernier volet de ce travail concerne l'utilisation directe d'allylalanes chiraux. Reposant sur la stabilité configurationnelle de ces alanes, un dédoublement cinétique des deux énantiomères, utilisant le camphre en tant que "piège chiral", permet d'enrichir le milieu réactionnel en un énantiomère. L'addition d'électrophiles prochiraux donne accès à des alcools et amines homoallyliquesénantio-enrichis. / This thesis deals with the use of chiral allylmetals, allylalanes and allylzincs, in asymmetric synthesis. Strategies adapted to the intrinsic configurational stability of these two species have been developed and applied to the synthesis of enantio-enriched homoallylic alcohols and amines.The first part of this manuscript is devoted to the generation of cycloalkylen-1-yl-zinc from the corresponding alanes via a titanium-catalyzed hydroalumination of conjugated dienes / transmetallation sequence. These allylzines, involved in the allylmetallation of non-racemic imines, provided the corresponding homoallylamines with good diastereoselectivity according to a dynamic kinetic resolution process.The first part of this memory discusses the generation of cycloalkylen-1-ylzincs from the corresponding alanes via a titanium-catalysed hydroalumination of cyclic conjugated dienes/transmetallation sequence. These allylzincs, involved in the allylmetallation of non-racemic imines, provided homoallylic amines with good diastereoselectivity according to a dynamic kinetic resolution process.The second part of this work aims at studying the influence of transmetallation co-products on the stereochemical course of the imine allylation reaction. The alternative use of allylzirconiums, which delivers a inert Lewis acid, was proven to benefit to the streoselectivity of the imine allylation.The last part of this work concerns the direct use of chiral allylalanes. Based on the configuration stability of these alanes, a kinetic resolution of the two enantiomers, using camphor as a "chiral trap", allowed to enrich the reaction medium with an enantiomer. The subsequent addition of prochiral electrophiles gives access to enantio-enriched homoallylic alcohols and amines.

Small molecule hydrogen bond donors have emerged as versatile catalysts in asymmetric synthesis. Within this class, chiral BINOL phosphoric acid is regarded as one of the pioneer catalysts used in several asymmetric transformations. The ability of the catalyst to activate the substrates could be controlled in two different ways. (1) Dual activation/bifunctional activation of substrate by hydrogen bond interactions or ion pairing with phosphoric acid or (2) By forming chiral BINOL phosphate metal complex that could significantly alter the interactions in chiral space. In particular, chiral alkaline earth metal phosphate complexes have unique advantages as catalysts owing to the ubiquitous availability of alkaline earth metals, strong Brønsted basicity of their counterions, mild but significant Lewis acidity of the metal and their ability to coordinate at multiple reactive sites due to large ionic radius. Chapter 1 summarizes the recent development of alkaline earth metal complexes in asymmetric catalysis. My thesis dissertation is focused on the application of chiral alkaline earth metal phosphate complexes in novel asymmetric reactions. In Chapter 2, we disclosed an efficient asymmetric one-pot synthesis of chiral 1,3-oxazolidines and chiral 1,3-oxazinanes. Chiral oxazolidines and oxazinanes are widely used as auxiliaries in asymmetric transition metal catalysis and also key structural motifs in natural products with biological activities. We developed a new synthetic method for chiral 1,3-oxazolidines which follows the enantioselective addition of alcohols to imines catalyzed by chiral 3,3’-(triisopropylphenyl)-derived BINOL magnesium phosphate to form hemiaminal intermediate, which then undergoes mild base mediated intramolecular nucleophilic substitution to afford highly enantioselective 1,3-oxazolidines and 1,3-oxazinanes in good yields. In Chapter 3, we developed the first catalytic enantioselective desymmetrization process for the synthesis of novel axially chiral cyclohexylidene oxime ethers. Even though these molecules were found to be optically active in 1910, methods to synthesize these molecules are scarce. We have developed an efficient desymmetrization process of 4-phenyl cyclohexanones with phenoxyamines catalyzed by chiral BINOL strontium phosphate complex to afford highly enantioselective products. We then extended this methodology to the dynamic kinetic resolution of 2-substituted cyclohexanones to form chiral 2-substituted cyclohexyl oximes in good enantioselectivities, as demonstrated in Chapter 4. We further demonstrated the utility of these compounds by converting them to chiral 2-aryl cyclohexylamines which are important synthetic intermediates.