Document incorrectly classified as a dissertation on title page (decision to classify as a thesis from NDSU Graduate School) / Organocatalysis is a field that has bloomed over the last decades. With the field’s promise of being able to mimic nature and afford products in a synergistic manner to traditional Lewis acid catalysis, several interesting discoveries have been made. Owing to the vastness of the field as it exists today, this document will focus on two main aspects; cinchona alkaloid (and derivatives) as used in common carbon-carbon bond forming reactions and kinetic resolution via 4-dimethyl aminopyridine-N-oxide derivative driven acylation. Kinetic resolution via organocatalysis has the potential to react one enantiomer of a racemic mixture without affecting the other. The highlight of this screening was an s factor of 9 which was produced using optimized conditions using a catalyst designated DMAPO-IV. There remains much to do in improving the system and elucidating the scope of this catalytic system this report details the efforts made thus far.

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Catalysis is an important field of study in chemical engineering and chemistry due to its application in a vast number of chemical transformations. Traditionally, catalysts have been developed as homogeneous molecular species or as heterogeneous insoluble materials. While homogeneous catalysts are typically very active and selective, they are difficult to recover. Conversely, heterogeneous catalysts are easy to recover and reuse, but they generally are less selective. To address these issues, the immobilization of homogeneous catalyst analogs onto solid supports has been a subject of research for the past few decades. Nonetheless, the effects of immobilization are still not completely predictable, and so continued effort is required to develop new immobilized catalysts as well as to develop a better understanding of how different parameters affect catalytic behavior. This dissertation presents the synthesis, characterization, and evaluation of new immobilized catalysts for different applications. First, a solid base catalyst supported on silica was developed and studied in the synthesis of cyclic carbonates from epoxides and carbon dioxide. Next, polymer and silica supported vanadium Schiff base catalysts were developed and evaluated for use in the oxidative kinetic resolution of alpha-hydroxy esters, an enantioselective reaction. Lastly, salen catalyst analogs with amine reactive functional groups were synthesized and characterized for grafting onto aminosilicas with different degrees of amine group isolation. The grafted catalysts were then tested to determine how catalyst spacing on the surface affects their behavior. Throughout the presentation of these results, comparisons are made amongst the new supported catalysts and relevant existing catalysts to discern general trends which could be applied to a wider range of immobilized catalysts. Finally, research opportunities for further improvements in these areas are suggested.

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.

Nesta dissertação de mestrado foram estudadas duas bactérias, Sphingobacterium sp e Arthrobacter atrocyaneus, produtoras de enzimas álcool desidrogenases que se mostraram capazes de catalisar reações de oxidação enantiosseletiva de alcoóis secundários racêmicos. Inicialmente foram avaliados alguns parâmetros para a realização da resolução cinética do (RS)-1-feniletanol, assim como quantidade de substrato, biomassa das bactérias (Sphingobacterium sp e Arthrobacter atrocyaneus) e tempo reacional necessário para a oxidação completa de um dos enantiômeros do substrato. Nas reações com a bactéria Sphingobacterium sp (R1AC23) observou-se a presença de álcool desidrogenase com alta atividade catalítica, porém com moderada enantiosseletividade, pois em alguns casos observou-se a oxidação completa dos alcoóis para-substituídos derivados do (RS)-1- feniletanol a suas correspondentes cetonas. Com o estudo das reações do (RS)-1-feniletanol e a bactéria Arthrobacter atrocyaneus (R1AF57) determinou-se os principais parâmetros reacionais para alcançar uma excelente resolução cinética. Sendo assim, aplicou-se essa metodologia para diferentes alcoóis secundários em dois meios reacionais diferentes: com células em crescimento e com células ressuspensas em tampão fosfato. A atividade catalítica foi mais eficiente com as células em crescimento com conversões próximas de 50% e excesso enantiomérico >99% na maioria dos casos, destacando-se os derivados do (RS)-1-feniletanol para e meta substituídos. Empregou-se a Arthrobacter atrocyaneus em testes de resolução cinética dinâmica (RCD). Como durante as reações de oxidação um co-produto é uma cetona, estudou-se o emprego in situ do NaBH4 como redutor desse composto. Com isso, tem-se um ciclo reacional de oxidação-redução. Sendo assim, por estereoinversão, foi possível alcançar rendimentos maiores que 50% do álcool enantiomericamente puro. Com o (RS)-1-(4-metilfenil)-etanol como substrato, obteve-se o álcool enantiomericamente puro com rendimento de 79% e excesso enantiomérico >99% / In this dissertation two bacterial strains were studied, Arthrobacter atrocyaneus and Sphingobacterium sp, which are alcohol dehydrogenases producers that were able to catalyse racemic secondary alcohols enantioselective oxidation. Initially, some reaction parameters to carry out the kinetic resolution of (RS)-1- phenylethanol were evaluated, such as substrate amount, bacterial biomass (Arthrobacter atrocyaneus and Sphingobacterium sp) and the reaction time for complete oxidation of one enantiomer of the substrate. In the reactions with Sphingobacterium sp (R1AC23) was observed the presence of alcohol dehydrogenase with high catalytic activity and moderate selective. Therefore, in some cases, the total oxidation of the both enantiomers of (RS)-1- phenylethanol para-substitued derivatives to the corresponding ketones were observed. By studying the reactions of (RS)-1-phenylethanol and Arthrobacter atrocyaneus (R1AF57), the reaction parameters to achieve excellent kinetic resolution were determined. Therefore, this methodology was applied to different secondary alcohols under two different reaction media: with growing cells and resting cells in phosphate buffer. The catalytic activity was more efficient with growing cells. The conversions were next to 50% and enantiomeric excess> 99% in most of the cases, especially those reactions with alcohols derived from (RS)- 1-phenylethanol para and meta substituted. Arthrobacter atrocyaneus was employed in dynamic kinetic resolution (DKR). As during the oxidation reactions, a ketone co-product is obtained, the use of NaBH4 was studied to reduce this compound in situ. Thus, an oxidation-reduction reactional cycle was achieved. Then, by estereoinversion it was possible to achieve yields higher than 50% of the pure enantiomerically alcohol. With (RS)-1-(4-methylphenyl)-ethanol as substrate, enantiomeric excess > 99% and yield 79% of pure enantiomerically alcohol was obtained

This thesis is divided into three parts, revolving around the developments of dynamic systems utilized in dynamic kinetic resolution (DKR) and constitutional dynamic chemistry (CDC). The first section gives an introduction to constitutional dynamics, the core concept of this thesis. Constitutional dynamics can be tuned through reversible interactions. Then, the basic principles of constitutional dynamics in DKR and CDC are discussed, along with their applications. The second section explores the asymmetric synthesis of oxazolidinone derivatives using lipase catalysis through kinetic resolution (KR) and dynamic kinetic resolution. In the first example, synthetic protocol to enantioenriched 5-phenyloxazolidin-2-ones is described, where a kinetically controlled carbamation is followed by lipase-catalyzed cyclization. In contrast to the 5-substituted species, the synthesis of 3-phenyloxazolidin-2-one derivatives could be achieved through lipase-catalyzed cascade O- and N- alkoxycarbonylations in one pot. Furthermore, this KR system could be coupled to a ruthenium-catalyzed racemization process of 1,2-aminoalcohols, thus providing an efficient DKR methodology for asymmetric transformations. The third section focuses on dynamic systems built through reversible covalent reactions. In the first example, a selective gelation process is described, and employed to resolve dynamic imine systems consisting of gelator candidates.  In the second example, reversible reactions with aldehyde enamines are presented, including enamine formation and exchange reactions. In particular, Bi(III) and Sc(III) were discovered to accelerate the enamine exchange reactions by 50-400 times, in which the equilibria could be reached within hours. The last example describes reversible nitroaldol reactions in aqueous media, where rapid and efficient equilibration was identified for selected structures in neutral phosphate buffer. / <p>QC 20150911</p>

Nesta dissertação de mestrado foram estudadas duas bactérias, Sphingobacterium sp e Arthrobacter atrocyaneus, produtoras de enzimas álcool desidrogenases que se mostraram capazes de catalisar reações de oxidação enantiosseletiva de alcoóis secundários racêmicos. Inicialmente foram avaliados alguns parâmetros para a realização da resolução cinética do (RS)-1-feniletanol, assim como quantidade de substrato, biomassa das bactérias (Sphingobacterium sp e Arthrobacter atrocyaneus) e tempo reacional necessário para a oxidação completa de um dos enantiômeros do substrato. Nas reações com a bactéria Sphingobacterium sp (R1AC23) observou-se a presença de álcool desidrogenase com alta atividade catalítica, porém com moderada enantiosseletividade, pois em alguns casos observou-se a oxidação completa dos alcoóis para-substituídos derivados do (RS)-1- feniletanol a suas correspondentes cetonas. Com o estudo das reações do (RS)-1-feniletanol e a bactéria Arthrobacter atrocyaneus (R1AF57) determinou-se os principais parâmetros reacionais para alcançar uma excelente resolução cinética. Sendo assim, aplicou-se essa metodologia para diferentes alcoóis secundários em dois meios reacionais diferentes: com células em crescimento e com células ressuspensas em tampão fosfato. A atividade catalítica foi mais eficiente com as células em crescimento com conversões próximas de 50% e excesso enantiomérico >99% na maioria dos casos, destacando-se os derivados do (RS)-1-feniletanol para e meta substituídos. Empregou-se a Arthrobacter atrocyaneus em testes de resolução cinética dinâmica (RCD). Como durante as reações de oxidação um co-produto é uma cetona, estudou-se o emprego in situ do NaBH4 como redutor desse composto. Com isso, tem-se um ciclo reacional de oxidação-redução. Sendo assim, por estereoinversão, foi possível alcançar rendimentos maiores que 50% do álcool enantiomericamente puro. Com o (RS)-1-(4-metilfenil)-etanol como substrato, obteve-se o álcool enantiomericamente puro com rendimento de 79% e excesso enantiomérico >99% / In this dissertation two bacterial strains were studied, Arthrobacter atrocyaneus and Sphingobacterium sp, which are alcohol dehydrogenases producers that were able to catalyse racemic secondary alcohols enantioselective oxidation. Initially, some reaction parameters to carry out the kinetic resolution of (RS)-1- phenylethanol were evaluated, such as substrate amount, bacterial biomass (Arthrobacter atrocyaneus and Sphingobacterium sp) and the reaction time for complete oxidation of one enantiomer of the substrate. In the reactions with Sphingobacterium sp (R1AC23) was observed the presence of alcohol dehydrogenase with high catalytic activity and moderate selective. Therefore, in some cases, the total oxidation of the both enantiomers of (RS)-1- phenylethanol para-substitued derivatives to the corresponding ketones were observed. By studying the reactions of (RS)-1-phenylethanol and Arthrobacter atrocyaneus (R1AF57), the reaction parameters to achieve excellent kinetic resolution were determined. Therefore, this methodology was applied to different secondary alcohols under two different reaction media: with growing cells and resting cells in phosphate buffer. The catalytic activity was more efficient with growing cells. The conversions were next to 50% and enantiomeric excess> 99% in most of the cases, especially those reactions with alcohols derived from (RS)- 1-phenylethanol para and meta substituted. Arthrobacter atrocyaneus was employed in dynamic kinetic resolution (DKR). As during the oxidation reactions, a ketone co-product is obtained, the use of NaBH4 was studied to reduce this compound in situ. Thus, an oxidation-reduction reactional cycle was achieved. Then, by estereoinversion it was possible to achieve yields higher than 50% of the pure enantiomerically alcohol. With (RS)-1-(4-methylphenyl)-ethanol as substrate, enantiomeric excess > 99% and yield 79% of pure enantiomerically alcohol was obtained

Muamvatin (30) is a polypropionate natural product isolated from Siphonaria normalis by Ireland et al. in 1986. Muamvatin (30) is made from eight propionate units and contains an extraordinary trioxaadamantane ring system. This ring system exists in only one other naturally occurring polypropionate known as caloundrin B. Regarding the rare muamvatin trioxaadamantane ring system, it was hypothesized this ring system may not be formed via an enzymatic process and the actual natural product could be the linear precursor ent-71 which cyclizes to muamvatin (30) during isolation. The first total synthesis of muamvatin (30) by Paterson et al. confirmed its absolute and relative configuration, but the ambiguity regarding the origin of the trioxaadamantane ring system in this molecule remains unresolved. This work describes two approaches to make the linear precursor ent-71 from triol ketone 153. The carbon skeleton of muamvatin was synthesized through two iterative diastereoselective aldol reactions. In the first approach, “the thiopyran route”, the diene moiety of aldehyde 73 required protection to avoid reduction during desulfurization. Although use of the tircarbonyliron complex was successful, the trihydroxy ketone revealed upon desulfurization was unstable and spontaneously cyclized to bicyclic acetal 156. Molecular mechanics revealed that the relative configurations embedded in C3, C7, and C8 dramatically effected the stability of the corresponding bicyclic acetal. With that lesson learned, the fully assembled linear precursor 197 was made in our second approach “the acyclic route”. The oxidation state of the backbone oxygens were manipulated via an unusual chemoselective double Swern oxidation. Finally, revealing the sensitive 5-hydroxy-3,7,9-trione functionality formed the precursor 202. Efficient cyclization of precursor 202 and removal of the protecting group at C11-OH produced the desired natural product 30. The cyclization conditions tested on the linear precursor 202, suggested that although the cyclization to the trioxaadamantane is strongly favored thermodynamically, the process is very slow and unlikely to occur during the isolation process. Thus, formation of the trioxaadamantane ring system could be an enzyme-mediated process as was concluded for caloundrin B.

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>

This thesis has been focused on enzymatic kinetic resolutions and stereoselective oxidative transformations of enallenes catalyzed by PdII. In the first part of the thesis, a detailed discussion on Candida antarctica lipase B (CALB)-catalyzed kinetic resolution (KR) of δ-functionalized alkan-2-acetates is shown. We gained a deeper insight into the mechanism of enzyme-substrate recognition. Changing from an anhydrous solvent to water or a water-containing organic solvent enhanced the enantioselectivity. The effect of –OH was also confirmed by a lipase mutant suggesting that the water molecule mentioned above can be partly mimicked. In the second part of the thesis, we developed an efficient KR for allenic alcohols. On this basis, a novel synthesis of optically pure 2-substituted 2,3-dihydrofurans from allenic alcohols via a Ru-catalyzed cycloisomerization was reported. The developed protocol enabled us to assemble an optically pure precursor for total synthesis with three chiral centers from readily available allenol in 2 days. In the third part, we reported a class of reactions involving C–H cleavage under mild conditions: PdII-catalyzed oxidative transformations of enallenes. These reactions are particularly attractive since a number of meticulous structures have been achieved from readily accessible starting materials. The directing effect of an unsaturated hydrocarbon was found to be key for these transformations. In the final part, we developed the carbonylative insertion reaction discussed in the third part of the thesis into an asymmetric version. By using this methodology, a number of cyclopentenone compounds were obtained in good to excellent enantioselectivity.