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>

Die Dissertation beschreibt die Herstellung von ringförmigen Verbindungen (Naphthalenophanen) mit Hilfe der Dehydro-Diels-Alder-Reaktion, wobei immer Enantiomerenpaare auftreten. Es wird der diastereoselektive Aufbau von Naphthalenophanen und der enantiomeren reine Aufbau von Biarylen untersucht. Desweiteren werden die physikalischen Eigenschaften der erhaltenen Verbindungen, wie die Phosphoreszenz, Trennbarkeit der entstehenden Enantiomere und die Ringspannung beschrieben. / The dissertation describes the synthesis of cyclic compounds (Naphthalenophanes) using the Dehydro-Diels-Alder reaction. The diastereoselective assembling of Naphthalenophanes and the development of pure enantiomeres were researched. All synthesised products are pairs of enantiomeres. Furthermore the physical properties like the phosphorescence, separability of the enantiomeres and the ring strain energy were specified.

Functionalized cyanophosphates are important starting materials for the synthesis of beta-lactam ring moiety of beta-lactam antibiotics. The cyanophosphates are synthesized starting from easily available acylphosphonate and ethylcyanoformate. Acylphosphonates are synthesized starting from acylchloride and trimethylphosphite. Addition of acylphoshonate to ethylcyanoformate furnishes the cyanophosphate with the quaternary center.

In this study new twelve phosphorus based chiral ligands were synthesized and characterized. Then the catalytic activity of these chiral ligands was tested with Cu(II) and Ag(I) salts in asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides. This method provides the synthesis of different pyrrolidine derivatives with up to four stereogenic centers. Pyrrolidine derivatives are found in the structure of many biologically active natural compounds and drugs. Therefore the asymmetric synthesis of these compounds is highly important and many groups are involved in this area. As the precursor of the azomethine ylides, N-benzyliden-glycinmethylester, N-(4-methoxy benzyliden)-glycinmethylester, N-(naphthalene-1-ylmethylene)-amino-acetic acid methyl ester, and N-(naphthalen-2-ylmethylene)-amino-acetic acid methyl ester were synthesized and used. As the dipolarophiles, methyl acrylate, dimethyl maleate and N-methyl maleimide were used. Using these imines and dipolarophiles with 6 mol % of one of the P-FAM chiral ligands in the presence of Ag(I) salt, pyrrolidine derivatives were synthesized in up to 95% yield and 89% enantioselectivity. Additionally, chiral ligand was recovered in more than 80% yield and reused without losing its activity.

This thesis focuses on the asymmetric reduction of N-protected derivatives of (3S)-3-amino-1-chloro-4-phenyl-2-butanone to their corresponding diastereomeric alcohol products, which are key intermediates in the synthesis of HIV protease inhibitors. Although the stereoselective synthesis of the (S,S) alcohol product is easily achieved, preparing the (R,S) diastereomer is much more challenging. I investigated three diastereoselective reduction processes: 1) Meerwein-Ponndorf-Verley (MPV) reduction, 2) asymmetric transfer hydrogenation, and 3) boron reducing agents. The diastereoselectivity of the MPV reduction still favored the (S,S) product; however, I discovered a significant rate enhancement when the standard catalyst (aluminum isopropoxide) was replaced with aluminum tert-butoxide. Many reaction variables were investigated in the asymmetric transfer hydrogenation reaction and the diastereoselectivity was improved to give a ratio of the desired (R,S) diastereomer to the undesired (S,S) alcohol of 9.5:1. Using chiral oxazaborolidine catalysts, an unprecedented (R,S) to (S,S) ratio of 9.5:1 was achieved. Finally, I investigated the effect of the N-protecting group on the stereoselectivity of the reduction. When the original boc-protecting group was replaced with a phthalimide group, the diastereoselectivity of the MPV reduction was reversed to favor the desired (R,S) product.

In this thesis manuscript are described our synthetic efforts and the first total synthesis of two natural products isolated from the sponges of the genus Plakortis. In total, two different synthetic approaches were studied to finally accomplish the synthesis of plakortolide I. The first approach is an extension of the method developed by our group which consists in the creation of the 1,2-dioxane cycle by intramolecular opening of vinyl epoxide with β-hydroperoxy group. Firstly, we was interested in the preparation of alkoxymethylhexa-2,5-dien-1-ol. We have also tried to create the 1,2-dioxane cycle by double opening of bis-1,5-epoxide with hydrogen peroxide. Further more we have synthesised trisubstituted β-hydroperoxy vinyl epoxide, precursor of 1,2-dioxan ring, from R-epichlorohydrin. During this synthesis a procedure of chemoselective methylenation of ketone in the presence of epoxide by Nysted reagent and Ti(OiPr)2Cl2 was developed. Finally, (-)-ent-plakortolide I and seco-plakortolide E were synthesised by intramolecular Michael addition of hydroperoxide to double bond of the butenolide moiety

Organosulfur compounds have been used by humans for centuries and played a pivotal role in shaping our history. The chemistry presented herein deals primarily with three distinct organic transformations involving organosulfur species. The three transformations are used in tandem to complete the synthesis of natural products. The first chapter examines a new diastereoselective alkylation reaction of sulfenate anions with stereoinduction provided by chiral amino iodides. A series of β-amino sulfoxides are accessed in good yields and selectivities from alkylations with the corresponding lithium arene- and E-1-alkenesulfenate anions. The relative reactivity of different electrophiles towards a selection of lithium sulfenate anions was also evaluated by performing competition experiments. In the second chapter 1,2-dibromotetrachloroethane (C2Br2Cl4) was evaluated as a more economical halogenating agent for the in-situ Ramberg-Bäcklund rearrangement (RBR). A series of trans-stilbenoids were successfully synthesized using this protocol in excellent yields. The new RBR system also worked well for dialkyl and cyclic substrates, but the reaction was plagued by polyhalogenation for hexyl benzyl sulfone. The methodology was extended to the formal total synthesis of natural polyphenol E-resveratrol. Chapter three investigates asymmetric aza-Michael reactions of chiral β-amino sulfoxides/sulfones to synthesize thiomorpholine S-oxides and S,S-dioxides, respectively. Remarkably, cyclizations of the β-amino sulfoxides provide the trans- 3,5-substituted heterocycles, while the β-amino sulfones provide the complementary cis-3,5-substituted heterocycles. The aza-Michael chemistry was exploited along with the sulfenate and RBR protocols to access two ant venom alkaloids. / NSERC

This thesis details investigations into the generation and synthetic utility of α,β-unsaturated acyl ammonium intermediates using isothioureas as Lewis base organocatalysts to generate a range of heterocyclic products. Initial investigations focussed on the development of a Michael addition-lactonisation protocol utilising α,β-unsaturated acyl ammonium intermediates (generated in situ from HBTM 2.1 and α,β-unsaturated homoanhydrides) and a range of 1,3-dicarbonyl nucleophiles. Products could be isolated as lactones or as ring-opened highly functionalised esters, giving good yields and excellent enantioselectivity. 1,3-Diketones were shown to generate a mixture of regioisomers and whereas 1,3-ketoesters afforded only a single regioisomer. A crystal structure of an α,β-unsaturated acyl ammonium intermediate was obtained that clearly demonstrated steric blocking of the Si- face of the alkene by the catalyst stereodirecting groups, therefore it can be postulated that enantiocontrol in the addition occurs by selective nucleophilic addition from the Re- face. α,β-Unsaturated acyl ammonium species were then shown to participate in asymmetric annulation processes with benzazole nucleophiles to afford highly functionalised heterocyclic products, with both lactone and lactam formation observed. The relationship between nucleophile structure and process regioselectivity was investigated and it was demonstrated that benzothiazole and benzimidazole nucleophiles afforded preferential N-cyclisation to give lactams whilst benzoxazoles exhibited O-cyclisation to form lactones. It was also possible to influence the regioselectivity by changing the electronic properties of the acyl group (R'). Due to the reactivity of this class of nucleophiles it was possible to access products with quaternary centres. Palladium-catalysed cross coupling reactions were also successful on 3-bromo substituted lactams, demonstrating the potential for further derivatising these interesting heterocyclic products. Finally, a cascade protocol was developed that employed Michael-Michael-lactonisation steps to give tricyclic products from enone malonate nucleophiles and α,β-unsaturated acyl ammonium intermediates (generated in situ by addition of HBTM 2.1 into acid chlorides). Interestingly, the reaction showed higher enantioselectivity at elevated temperatures (70 ˚C) and moderate regioselectivity (1,4- vs. 1,2-addition), which could not be improved after extensive screening. A range of lactones was isolated in moderate yields and enantioselectivity.

Les amphidinols sont une nouvelle classe de molécules naturelles de type polycétide dont l’amphidinol-3 est la seule molécule possédant sa structure entièrement établie. L’amphidinol-3 exhibe les meilleures activités biologiques de cette famille, principalement antifongique ethémolytique. La synthèse du fragment C17-C30 a été le premier objectif de ces travaux de thèse. Cette synthèse est basée sur l’utilisation du para-tolylsulfoxyde comme auxiliaire de chiralité et d’un bromoallylsilane comme corps central. Tous les centres asymétriques sont contrôlés avec de très hauts rapports diastéréomériques à l’exception de la configuration du méthyle en C23. La non-maîtrise de ce centre, ainsi que des difficultés probables de couplage nous ont obligés à repenser notre stratégie. Suite au changement rétrosynthétique, la synthèse du fragment C13-C29 a été réalisée. L’étape clef de cette voie synthétique est alors le couplage entre l’anion lithié d’un dérivé de 1,3-dithiane avec un aldéhyde α-branché. Après de nombreux ajustements de groupements protecteurs, le fragment C13-C29 est obtenu avec tous ses centres asymétriques maîtrisés. / Amphidinols are a new class of polyketide extracted from dinoflagellates and exhib promising biological activities, such as antifungal and hemolytic. The amphidinol-3 is the only amphidinol possessing its fully elucidated structure and is the most biologically potent.The C17-C30 fragment is the first goal of our research. The synthesis is based on sulfoxide as chiral auxiliary and on a bromoallylsilane as bifunctionnal central core. All stereogenic centers are fully controlled with high diastereomeric ratios except the one bearing a methyl in C23 position. The lack of selectivity during the hydrogenation affording the C23 stereogenic center and plausible failures of fragment couplings force us to explore a new retrosynthesis. Our second goal is the synthesis of C13-C29 fragment. The new strategy is based on a coupling between a 1,3-dithiane derivative and an α-branched aldehyde. After protecting group optimization, the C13-C29 fragment is synthetized with all its stereogenic centers fully controlled.

Ce travail de thèse porte dans une première partie sur le développement d’une réaction de type Reformatsky asymétrique appliquée à la synthèse de motifs « 2-méthyl-1,3-aminoalcools » syn, syn et syn, anti. Cette réaction met à l’honneur la chimie des sulfoxydes chiraux dont la présence sur le substrat permet de construire trois centres asymétriques contigus. En effet, dans une première étape, une réaction de type Reformatsy entre un précurseur chiral, un γ-bromo-β-cétosulfoxyde et différentes imines permet de former les deux premiers centres asymétriques. La sélectivité favorise de composé syn. Cette réaction est très sélective avec des sélectivités syn/anti allant jusqu’à 100/0. Ensuite, une réduction diastéréosélective des β-cétosulfoxydes obtenus à l’issue de la réaction de Reformatsky permet de former le troisième centre asymétrique avec une diastéréosélectivité totale. Ainsi, l’utilisation du DIBAL-H seul permet d’obtenir l’aminoalcool 1,3-syn alors que l’utilisation du système DIBAL-H/Yb(OTf)3 permet d’accéder à l’aminoalcool 1,3-anti avec dans les deux cas une diastéréosélectivité totale pour cette étape de réduction.Dans une deuxième partie, ce travail de thèse présente des avancées vers la synthèse totale du (+)-triènomycinol, une molécule naturelle à forte activité cytotoxique. Il s’agit d’un macrolactame à 21 chaînons comportant une partie triènique, une liaison peptidique, une stéréotriade syn, anti et un centre asymétrique isolé. La stratégie proposée consiste à construire tous les centres asymétriques en utilisant la chimie des sulfoxydes chiraux. En effet, la stéréotriade a été construite en utilisant la réaction dévloppée dans la première partie, à savoir une réaction de type Reformatsky asymétrique couplée à une réduction diastéréosélective à l’aide du système DIBAL-H/Yb(OTf)3. Le centre stéréogène isolé a lui aussi été construit grâce à la chimie des sulfoxydes chiraux, par réduction diastéréosélective d’un β-cétosulfoxyde à l’aide de DIBAL-H. Cette molécule a été découpée en deux fragments, un fragments « ouest » et un fragment « est » qui ont été couplés. De nombreuses étapes ont au préalable été mises au point sur un composé modèle. Par manque de temps et de matière, la synthèse totale du (+)-triènomycinol n’a pu être achevée. / In a first part, the aim of this PhD thesis was to develop an asymmetric Reformatsky type reaction for the synthesis of “2-methyl-1,3aminoalcohol” moieties. This reaction is based on the chemistry of chiral sulfoxides. Indeed, in a first step, an asymmetric Reformatsky type reaction between a γ-bromo-β-ketosulfoxide and different imines allows us to build two contiguous stereogenic centers. This reaction is very selective with a syn/anti selectivity reaching up to 100/0. In a second step, the β-ketosulfoxides obtained after the Reformatsky-type reaction were diastereoselectively reduced using either DIBAL-H or the system DIBAL-H/Yb(OTf)3 to afford the third stereogenic center with a total diastereoselectivity. To sum up, the use of DIBAL-H allowed us to obtain the aminoalcohol 1,3-syn, whereas the use of the system DIBAL-H/Yb(OTf)3 allowed us to synthesize the aminoalcohol 1,3-anti with a perfect diastereoselectivity in both cases.In a second part, this PhD thesis focused on the total synthesis of natural cytotoxic molecule, (+)-trienomycinol. This molecule is a macrolactam containing a syn, anti stereotriad, an isolated stereogenic center and a trienic unit. The proposed strategy was based on the use of chiral sulfoxides. The stereostriad was built using the strategy developed in the first part, the asymmetric Reformatsky reaction followed by a diastereoselective reduction with the system DIBAL-H/Yb(OTf)3. The isolated stereocenter was obtained by diastereoselective reduction of a β-ketosulfoxide with DIBAL-H. This molecule was divided into two parts: the “west” part and the “east” part which were coupled together. Many steps were first optimized on a model compound. Due to a lack of time and quantity, the total synthesis of (+)-trienomycinol could not be achieved.