This doctoral thesis was focused on the design and synthesis of novel chiral ligands for application in asymmetric catalysis. One of the best examples of asymmetric catalysis is the asymmetric hydrogenation reaction for its atom economy, ease of access to both S and R enantiomers and almost ultimate enantiomeric excess obtainable in a multitude of substrates. There has been much investigation into this reaction and there has been a plethora of chiral ligands designed which catalyze this reaction in high enantiomeric excess using metals such as rhodium, iridium and ruthenium. The vast majority of these ligands are diphosphines with their chirality lying either on the backbone of the ligand or on the coordinating phosphorus atom itself. In the beginning of this work investigation was undertook to explore the possibility of successfully employing a new type of ligand class in the asymmetric hydrogenation reaction, namely the N-phosphino sulfinamide or PNSO ligands. PNSO ligands had been successfully applied to the asymmetric Pauson-Khand reaction in the Riera group yielding cyclopentenone Pauson-Khand adducts in high yield and very high enantioselectivity. The family of PNSO ligands prepared in the Riera group was attractive because apart from the high yields and enantioselectivities obtained from the reactions in which they were used, they proved to be easily prepared in short syntheses from commercially available starting materials. It was believed if they could be successfully applied in asymmetric hydrogenation for their ease of preparation they would be an attractive alternative to the diphosphine ligand class. Unfortunately the first two PNSO-Rh complexes successfully prepared provided low enantioselectivities and difficulties were encountered while trying to prepare further analogues. After some time trying to achieve PNSO-Rh complex analogues unsuccessfully the direction of the project was shifted away from the N-phosphino sulfinamide ligand class in asymmetric hydrogenation. The MaxPhos ligand had recently been developed in the group and had proven highly promising. A study was demanded of its substrate scope as applied in rhodium catalyzed asymmetric hydrogenation. Substrates already described in the literature were prepared and the asymmetric hydrogenation of them catalyzed by the MaxPhos-Rh precatalyst was performed and conditions to do so were optimized. Of seven substrates prepared the MaxPhos-Rh proved to hydrogenate five of those with high enantioselectivity. The TOF of the MaxPhos rhodium catalyst applied in the hydrogenation of the Z-MAC substrate was examined by monitoring the flux of hydrogen and was calculated at 0.065 s-1. MaxPhos complexes of cobalt and palladium were prepared to form part of the investigation into widening the reaction scope of the ligand. [(MaxPhos)Co2(CO)4(C2H2)] proved to catalyze the Pauson-Khand reaction of norbornadiene and 1-hexyne with 24 % yield and 28 %, a noteworthy enantiomeric excess for the catalytic asymmetric Pauson-Khand reaction. Chalcogenated derivatives of MaxPhos were prepared. The diselenide was used to explore the electronic nature of the ligand. The MaxPhos-rhodium carbonyl stretching was examined. MaxPhos-BH3 was used to prepare mono-chalcogenated MaxPhos derivatives. They were applied also in asymmetric hydrogenation once complexed to rhodium but enantiomeric excess of no more than 21 % was obtained in the hydrogenation of the substrate Z-MAC. The aminophosphine, a chiral building block and key intermediate in the preparation of the MaxPhos ligand, was used in the attempt to prepare bulky chiral amidine ligands and although two such species were prepared they proved inapplicable in asymmetric catalysis. / Se desarrollaron los ligandos N-fosfino sulfinamida (PNSO) en el grupo de Riera para su aplicación en la reacción Pauson-Khand asimétrica. Se probaron que estos ligandos eran muy eficaces en esta reacción y daban rendimientos y enantioselectividades muy altos de los aductos Pauson-Khand. Probar la eficacia de estos ligandos PNSO en hidrogenación asimétrica formó parte de este trabajo. Se prepararon dos ligandos PNSO, se complejaron con rodio formando complejos neutros. Se protonaron los complejos neutros con ácido tetraflorobórico para formar los complejos catiónicos. Se usaron estos complejos de rodio- PNSO, tanto los complejos neutros como los catiónicos como catalizadores en la hidrogenación asimétrica del sustrato Z-MAC. Los complejos de rodio con el ligando PNSO substituido por el grupo tolilo en azufre no hidrogenaba el sustrato pero los complejos de rodio con el ligando PNSO dotado de tres grupos tert-butilos hidrogenaba el sustrato aunque con baja selectividad. Después de un tiempo intentando conseguir análogos de ligandos tipo PNSO sin éxito se cambió la dirección del proyecto. Se decidió centrarse en el ligando MaxPHOS el cual había sido desarrollado recientemente en el grupo Riera. El ligando MaxPHOS demostró gran eficacia en hidrogenación asimétrica con dos sustratos pero se deseaba un estudio mas amplio del potencial del ligando así que se sintetizaron siete sustratos y se probó el catalizador MaxPHOS en la hidrogenación asimétricas de esos sustratos. El catalizador MaxPHOS-Rh proporcionó excesos enantioméricos muy altos en cinco de los siete sustratos. Se hizo un estudio de las propiedades electrónicas del ligando MaxPHOS aprovechando los estudios de (31)P RMN y el MaxPHOS diselenuro lo cual se preparó anteriormente. También se estudió el “stretching” carbonilo del complejo MaxPHOS-Rh. Se demostró que el ligando MaxPHOS era menos rico en electronos que el ligando trichickenfootphos. Se prepararon complejos de MaxPHOS con paladio y cobalto para examinar la eficacia del ligando en reacciones mas allá de hidrogenación asimétrica como la reacción Pauson–Khand catalítica asimétrica. Se sintetizaron varios derivados del ligando MaxPHOS a partir de los intermedios clave en la preparación del ligando y se probaron en hidrogenación asimétrica proporcionando excesos enantioméricos bajos.

<p>This thesis describes the development of new methods for thepreparation of enantiomerically pure methyl branched alkylcompounds and their use as building blocks in the synthesis ofstereoisomerically pure pheromones of pine sawflies.</p><p>The high regioselectivity, enantioselectivity and activityof lipases in organic solvent in conjunction withenvironmentally compatible reaction conditions have madelipase-catalysed synthesis an attractive alternative toconventional synthetic methods in organic chemistry. The lipasefrom<i>Pseudomonas cepacia</i>(PCL) was used in kineticresolutions of primary 2- methylalcohols by acylation of thealcohols with vinyl acetate/vinyl butyrate. For alcoholsstudied, PCL showed moderate enantioselectivity<i>(E</i>= 10-20) towards 3-alkyl- or 3- cycloalkylsubstitutedprimary 2-methylpropanols, whereas 3-aryl-2-methyl-1-propanolswere accepted with high E-values<i>(E</i>>100).</p><p>Esterification of substituted methylcarboxylic acids withprimary alcohols catalysed by<i>Candida rugosa</i>lipase (CRL) was found to be anenantioselective reaction. In general, CRL showed highselectivity towards<i>(</i>S)-2-methylcarboxylic acids<i>(E</i>= 15-70) and also towards<i>(</i>R)-3-methylcarboxylic acids<i>(E</i>= 15-40). For substrates having a double bond located5-6 bonds from the carbonyl moiety a two-fold enhancement ofenantioselectivity value<i>(</i>E-value) was obtained compared to their saturatedanalogues,<i>E</i>≈ 15-25.</p><p>Furthermore, the enantioselectivity of CRL towards a seriesof 3- to 8-methyldecanoic acids were studied. CRL surprisinglyshowed enantiorecognition for all of these acids within theE-value range of 2.3-68. Interestingly, whereas the lipaseshowed S-preference when the methyl group was situated ateven-numbered carbons, R-preference was observed for thesubstrates with the methyl group at odd-numbered carbons.</p><p>In order to establish the stereoisomeric composition of thenatural sex pheromone of the pine sawfly<i>Microdiprion pallipe</i>s, all sixteen individual isomers of3,7,11-trimethyl-2-tridecanol (and their propionate esters)found in this species were synthesised in highdiastereoisomeric purities, 95.3-97.6%. The syntheses werebased on six enantiomerically pure building blocks, the fourstereoisomers of 1-lithio-2,6-dimethyloctane and the twoenantiomers of<i>ci</i>s-3,4- dimethyl-g-butyrolactone.</p><p><b>Keywords:</b>lipase,<i>Pseudomonas cepaci</i>a,<i>Candida rugos</i>a, enantioselective, enantiomeric ratio,primary 2-methylalcohol, substituted-methylcarboxylic acid,pine sawfly,<i>Microdiprion pallipe</i>s, sex pheromone,3,7,11-trimethyl-2-tridecanol, stereoisomer.</p>

Ziel der durchgeführten Arbeiten war die Etablierung neuer Synthesestrategien zur Gewinnung chiraler metall-organischer Gerüstverbindungen (engl: Metal-Organic Frameworks, MOFs). Hierfür wurden drei verschiedene Ansätze verfolgt. Zunächst sollte die Einbringung einer chiralen Dicarbonsäure mit einem 2,2´-Spirobiindan-Gerüst in ein MOF-Netzwerk untersucht werden. Im Rahmen einer Kooperation wurden neue mit chiralen Oxazolidinonen substituierte 4,4´,4´´-Benzol-1,3,5-triyl-tribenzoesäuren H3ChirBTB-n (n = 1, 2) entwickelt, die ebenfalls zur Synthese neuer chiraler MOFs dienten. Die Modifizierung bekannter nicht-chiraler metall-organischer Gerüstverbindungen mit koordinativ ungesättigten Metallatomen durch Anbindung chiraler Amine stellte die dritte Synthesestrategie dar. Im Rahmen der letztgenannten Syntheseroute wurde für MIL-101 (MIL = Matérial Institut Lavoisier) eine sehr hohe katalytische Aktivität in der Cyanosilylierung von Benzaldehyd nachgewiesen. Die Umsetzung mit chiralen Aminen führte jedoch nicht zu einem enantioselektiven Katalysator. Im Gegensatz dazu konnten die ersten beiden Synthesewege zur Gewinnung neuer chiraler metall-organischer Gerüstverbindungen erfolgreich beschritten werden. Durch solvothermale Reaktion von (S)-2,2´-Spirobiindan-5,5´-dicarbonsäure ((S)-H2Spiro-BIDC) mit Zinknitrat in N,N-Dimethylformamid (DMF) wurde eine neue chirale metall-organische Gerüstverbindung namens DUT-7 (DUT = Dresden University of Technology) der Zusammensetzung Zn4O((S)-Spiro-BIDC)3 dargestellt. Neben einer unerwarteten, zweifach interpenetrierten Netzwerkstruktur mit hexagonalen Kanälen weist DUT-7 eine für MOFs bislang noch nicht beobachtete temperaturinduzierte, reversible Strukturänderung auf. Die zweite neue Strategie zur Gewinnung chiraler MOFs beinhaltete die Umsetzung der chiralen Tricarbonsäuren H3ChirBTB-n, die entweder (S)-4-iso-Propyl- (n = 1) oder (S)-4-Benzyl-1,3-Oxazolidin-2-on-Substituenten (n = 2) tragen. Die beiden gewonnenen Verbindungen Zn3(ChirBTB-1)2 und Zn3(ChirBTB-2)2 weisen trotz gleicher Zusammensetzung völlig unterschiedliche Kristallstrukturen auf. Beide Materialien wurden erfolgreich in der Mukaiyama-Aldol-Reaktion von Benz- bzw. 1-Naphthaldehyd mit 1-Methoxy-2-methyl-1-(trimethylsiloxy)propen eingesetzt, wobei ihre katalytische Aktivität mit verschiedenen Referenzkatalysatoren verglichen wurde. Die erzielten Enantiomerenüberschüsse (ee) liegen zwischen 6 und 16%. Auf der Suche nach neuen, für die Einbringung der ChirBTB-n-Liganden geeigneten MOF-Strukturen wurde auch die Umsetzung der reinen, nicht chiralen 4,4´,4´´-Benzol-1,3,5-triyl-tribenzoesäure (H3BTB) untersucht. Die Reaktion mit Nickelnitrat führte zur Bildung einer neuen hochporösen Verbindung namens DUT-9 mit der Zusammensetzung Ni5O2(BTB)2(DEF,DMF)4(H2O)4. DUT-9 weist neben den auf dem Gebiet der MOF-Forschung bislang unbekannten Ni5O2-Clustern eine noch nicht beschriebene dreidimensionale (3,6)-Netzwerktopologie auf. Das neue Material zeigt zudem exzellente Speicherkapazitäten für Wasserstoff, Methan und Kohlenstoffdioxid. / The present work aims on the search for new synthesis strategies towards chiral Metal-Organic Frameworks (MOFs). Three different approaches were pursued. Initially, the integration of a chiral dicarboxylic acid with a 2,2´-spirobiindane backbone into a MOF network was investigated. Within a cooperation, new 4,4´,4´´-benzene-1,3,5-triyl-tribenzoic acids H3ChirBTB-n (n = 1,2) with chiral oxazolidinone substituents were developed which were also used for the assembly of chiral MOFs. The third synthesis strategy involved the tethering of chiral amines to coordinatively unsaturated metal atoms of known non-chiral Metal-Organic Frameworks. Within the last-mentioned approach, the very high catalytic activity of MIL-101 (MIL = Matérial Institut Lavoisier) towards the cyanosilylation of benzaldehyde was demonstrated. Treatment with chiral amines did not lead to an enantioselective catalyst. In contrast, the first two synthesis strategies could be performed successfully. A new MOF named DUT-7 (DUT = Dresden University of Technology) with composition Zn4O((S)-Spiro-BIDC)3 was obtained by solvothermal reaction of (S)-2,2´-spirobiindane-5,5´-dicarboxylic acid ((S)-H2Spiro-BIDC) with zinc nitrate in N,N-dimethylformamide (DMF). Besides an unexpected, two-fold interpenetrated framework structure with hexagonal channels, DUT-7 shows a temperature induced, reversible structure transformation not yet observed. The other new strategy to obtain chiral Metal-Organic Frameworks involved the conversion of the chiral tricarboxylic acids H3ChirBTB-n bearing either a (S)-4-iso-propyl- (n = 1) or a (S)-4-benzyl-1,3-oxazolidin-2-one substituent (n = 2). Though having the same framework composition, the new compounds Zn3(ChirBTB-1)2 and Zn3(ChirBTB-2)2 exhibit completely different crystal structures. Both materials were tested in the Mukaiyama aldol reaction between benzaldehyde or 1-naphthaldehyde, respectively, and 1-methoxy-2-methyl-1-(trimethylsiloxy)propene and their catalytic activity was compared to different reference catalysts. Enantiomeric excess values (ee) between 6 and 16% were obtained. In search of new MOF structures being suitable for the integration of the ChirBTB-n linkers, the conversion of the pure, non chiral 4,4´,4´´-benzene-1,3,5-triyltribenzoic acid (H3BTB) was investigated. The reaction with nickel nitrate lead to the formation of a new, highly porous compound Ni5O2(BTB)2(DEF,DMF)4(H2O)4 named DUT-9. Besides Ni5O2 clusters which are a novelty in MOF chemistry, DUT-9 exhibits a three dimensional (3,6)-network topology not yet described. In addition, the new material shows excellent storage capacities for hydrogen, methane and carbon dioxide.

This thesis is divided into three main results chapters that reflect the path my research took. In the first results chapter, the first organocatalyst for the carbonyl-ene reaction was discovered and found to give high conversion using 1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea. Various carbonyl and alkene precursors were examined in the ene reaction in both catalysed and uncatalysed reactions. It was found that ene reactions using fluoral and ethyl trifluoropyruvate give higher rates of reaction when compared to other carbonyl compounds. A novel enantiopure thiourea was synthesised and the ene reaction was catalysed enantioselectively to 33% e.e. In an attempt to catalyse the reaction to a further extent a new thiourea bonded to a P(=S)R2 group was developed. However, the intramolecular hydrogen bonding of this catalyst was thought to be so strong that this it did not catalyse the reaction. The synthesis of a chiral phosphoric acid was achieved but this was an unsuccessful catalyst in the ene reaction. Two component achiral thiourea and chiral acids were also examined in the ene and Mannich-type reaction. The new easily synthesised thiourea for this reaction has an interesting intermolecular hydrogen bonding coordination in the solid state. Asymmetric fluorination of ketoesters using palladium is a dynamic kinetic resolution. In the 2nd chapter cationic palladium complexes were synthesised and used to determine the optimum parameters for bidentate ligands in this reaction. Four carbon chain phosphines were found to give the highest conversion for this reaction among those ligands tested such as 1,4-bisdiphenylphosphinobutane (bite angle 99º). A new bis-phosphinous amide chiral ligand was developed with a bite angle of 96.7º. The dichloropalladium complex of this phosphine was isolated and structurally characterised. The use of the palladium complex in asymmetric fluorination was attempted however this was found to be unsuccessful. Mechanistic studies reveal that the formation of the desired cationic catalyst did not occur under conditions shown to work well for other palladium phosphine complexes. The ligand was investigated further in hydrogenation reactions. The phosphinous amide was protected as its borane and was used in the rhodium catalysed hydrogenation of alkenes to give high conversion and up to 93% e.e. The borane protected phosphinous amide was also found to catalyse the hydrogenation of acetophenone using copper complexes with up to 84% e.e for the hydrogenation of acetophenone, although conversion was quite low.

No description available.

Chapter I deals with novel approaches for α-amino acids. This chapter has been divided into three sections. Section A describes the synthesis of α-amino acids via the Beckmann rearrangement of carboxyl-protected β-keto acid oximes. The synthesis of α-amino acids using the Beckmann rearrangement involves the preparation of the Z-oxime and efficient protection of the carboxyl group. Various 2-substituted benzoylacetic acids were synthesized, in which the carboxyl function was masked as a 2,4,10-trioxaadamantane unit (an orthoacetate), and were converted to their oximes (Scheme 1).1 The oximes were converted to the their mesylates, which underwent the Beckmann rearrangement with basic Al2O3 in refluxing CHCl3. The corresponding 2-substituted-N-benzoyl-α-amino orthoacetates were obtained in excellent overall yields. In Section B, the synthesis of α-amino acids via the Hofmann rearrangement of carboxyl-protected malonamic acids is described. The Hofmann rearrangement involves the migration of the alkyl moiety of the amide onto the N-centre. Various 2-substituted malonamic acids (malonic acid mono amides) were synthesized with the carboxyl group masked as a 2,4,10¬trioxaadamantane unit (an orthoacetate). These underwent the Hofmann rearrangement with phenyliodoso acetate and KOH/MeOH (Scheme 2). The resulting (N-methoxycarbonyl)¬trioxaadmantylmethylamines (carbamates) were formed in yields > 90%, and are α-amino acids with both carboxyl and amino protection.2 In Section C, an approach to chiral amino acids via the reductive amination of ketones, involving the hydride reduction of 1-(S)-phenethyl amine derived Schiff bases of C-protected α¬keto acids is described. An efficient synthesis of α-amino acids has thus been developed in high diastereoselectivity. Various 1-acyl-2,4,10-trioxaadamantanes were prepared from the corresponding 1-methoxycarbonyl derivatives, via conversion to the N-acylpiperidine derivative followed by reaction with a Grignard reagent in refluxing THF (Scheme 3). These α-keto orthoformates were converted to corresponding imines with 1-(S)-phenethyl amine (TiCl4/Et3N/toluene/reflux), the Schiff bases being reduced with NaBH4 (MeOH/0 °C) to the corresponding 1-(S)-phenethyl N-alkylamines (diastereomeric excess by NMR ~ 90:10).3 Hydrogenolysis of the phenethyl group (Pd-C/H2/MeOH) finally led to the (aminoalkyl)trioxaadamantanes, which are chiral C-protected α-amino acids, in excellent overall yields. Here a mild, inexpensive and efficient hydride reducing agent for the reductive amination of α-keto acids has been developed. Chapter II deals with the enantioselective synthesis of piperidines and its applications in the synthesis of piperidine alkaloids.4 This chapter has been divided into two sections. In Section A, the enantioselective synthesis of 2-substituted piperidines and its applications in the synthesis of (R)-(-)-coniine and (R)-(+)-anatabine are described. Various N-tert-butylsulfinyl imines were synthesized, which upon allyl Grignard addition followed by N-allylation gave the diallyl compound with good diastereoselectivity (Scheme 4). The diallyl compound underwent ring closing metathesis with Grubbs’ first generation catalyst and subsequent reduction of the double bond with H2-Pd/C, furnished N-sulfinyl-2-susbstituted piperidines. Using this methodology (R)¬(-)-coniine hydrochloride and (R)-(+)-anatabine were synthesized. In Section B, the enantioselective synthesis of (S)-tert-butyl 2-(2¬hydroxyethyl)piperidine-1-carboxylate and its elaboration to the synthesis of (S)-(+)-δ-coniceine and (S)-(+)-pelletierine are described. The (S)-tert-butyl 2-(2-hydroxyethyl)piperidine-1¬carboxylate is a synthon used for the synthesis of various 2-substituted piperidine natural products. Using the above methodology (S)-tert-butyl 2-(2-hydroxyethyl)piperidine-1¬carboxylate was synthesized starting from (S)-(+)-2-methyl-2-propanesulfinamide and 3¬(benzyloxy)propanal (Scheme 5). This alcohol was further elaborated to furnish two piperidine alkaloids (S)-(+)-pelletierine and (S)-(+)-δ-coniceine. Scheme 5. Enantioselective synthesis of (S)-tert-butyl 2-(2-hydroxyethyl)piperidine-1¬carboxylate, (S)-(+)-pelletierine and (S)-(+)-δ-coniceine. Chapter III deals with the formation of barbituric acid in an aprotic medium and related mechanistic studies. The generally accepted mechanism for the formation of barbituric acid involves the nucleophilic attack of urea anion on diethyl malonate.5 This is debatable for at least two reasons: (1) the normally employed base, sodium ethoxide, is too weak to deprotonate urea and (2) diethyl malonate is more acidic than urea, so the initial deprotonation by base has to be from diethyl malonate. When diethyl malonate (DEM) enolate was treated with urea in DMF, barbituric acid was formed in 61% yield. The reaction was also extended to several 2-substituted DEM derivatives, the corresponding substituted barbituric acids being formed in reasonable yields. The reaction between diethyl 2-(ethoxycarbonyl)malonate and urea, with potassium carbonate in refluxing ethanol, led to the formation of barbituric acid. This is apparently facilitated by hydrogen bonding involving the enolate oxygen atom, which renders one of the carbonyl groups relatively electrophilic (Scheme 6). Meldrum’s acid failed to react with urea, despite its greater acidity, indicating that the reaction requires the formation of the E from of the s-trans enolate ion, in which the hydrogen bonding interaction and nucleophilic attack can occur in concert. Scheme 6. Proposed transition state for formation of Barbituric acid. Chapter IV deals with an improved Erlenmeyer synthesis with 5-thiazolone and catalytic manganese (II) acetate for aliphatic and aromatic aldehydes. A serious limitation to the classical Erlenmeyer reaction is that it generally fails in the case of aliphatic aldehydes. This chapter describes a convenient approach to this problem that extends the scope of the Erlenmeyer synthesis. The present study was aimed at developing milder conditions for the synthesis of 4¬arylidene and alkylidenethioazlactones. Thus, N-(thiobenzoyl)glycine was treated with DCC in DCM at room temperature for 10 min., according to a reported procedure, to form the thioazlactone.6 The same reaction mixture was treated with catalytic Mn(II) acetate and an equivalent of an aromatic aldehyde, to furnish the corresponding 4-arylidenethioazlactones in good yields. The scope of the reaction was extended to alphatic aldehydes also under similar reaction conditions, to obtain the 4-alkylidene thioazlactones in good to moderate yields (Scheme 7). Scheme 7. The Erlenmeyer synthesis with 5-thiazolone and manganese acetate. (for figures & structural formula pl refer pdf file)

The thesis entitled “Organocatalytic Cascade Cyclizations for the Enantioselective Synthesis of Spirooxindoles” is divided into three chapters. Chapter 1: Catalytic Enantioselective Michael Addition/Cyclization Cascade of 3-Isothiocyanato Oxindoles with Nitroolefins A myriad of spirocyclic frameworks present in natural product, and pharmaceutically important compounds, has attracted the synthetic organic chemists to explore their preparation in enantioselective manner. Consequently various strategies have been devised for efficiently accessing highly functionalized spirooxindoles. Among these strategies, the use of 3-isothiocyanato oxindoles as the building block appeared as the most popular one. The combination of 3-isothiocyanato oxindoles and a variety of electrophiles have already been reported. However one of the most popular electrophiles, nitroolefins, has never been used in the reaction with 3-isothiocyanato oxindoles. In this chapter, a highly efficient catalytic asymmetric Michael addition/cyclization cascade reaction between 3-isothiocyanato oxindoles and β-substituted nitroolefins with the help of a cinchonidine-derived bifunctional thiourea catalyst has been discussed. Highly functionalized spirooxindoles containing three successive stereocenters were obtained in high yield with moderate to good diastereo- and enantioselectivity. Reference: Kayal, S.; Mukherjee, S. Eur. J. Org. Chem. 2014, 6696-6700. Chapter 2: Catalytic Aldol-Cyclization Cascade of 3-Isothiocyanato Oxindoles with α-Ketophosphonates for the Enantioselective Synthesis of β-Amino-α-Hydroxyphosphonates The oxindole scaffold containing a quaternary stereocenter at the C3 position is a privileged structural motif present in many biologically active molecules and natural products. In this respect, spirooxindoles have received special attention during the past few years. Similarly, β-Amino and/or hydroxy functionalized phosphonic acids and their derivatives are found to display inhibitory activities towards a range of enzymes such as renin, HIV protease, thrombin, and various classes of protein tyrosine kinases and phosphatases. Considering the importance of both oxindole and β-amino-α-hydroxyphosphonic acid, we reasoned that highly functionalized phosphonic acid derivatives based on a spirooxindole framework could be of potential biological significance, if synthesized in enantiopure form This chapter deals with a cascade aldol-cyclization reaction between 3-isothiocyanato oxindoles and α-ketophosphonates for the enantioselective synthesis of spirooxindole-based β-amino-α-hydroxyphosphonate derivatives. Catalyzed by cinchona alkaloid-based bifunctional thiourea derivatives, this protocol delivers 2-thioxooxazolidinyl phosphonates bearing two adjacent quaternary stereogenic centers, generally in high yields with excellent diastereo- and enantioselectivities. Both the product enantiomers are accessible with nearly equally high level of enantioselectivity. Reference: Kayal, S.; Mukherjee, S. Org. Lett. 2015, 17, 5508-5511. Chapter 3: Catalytic Michael Addition/Cyclization Cascade of 3-Isothiocyanato Oxindoles with Cyclic α,β-Unsaturated Ketones: A Concise Enantioselective Synthesis of Bispiro[indoline-3,2'-pyrrolidine] Among different spirocyclic cores, the spirooxindole framework containing pyrrolidinyl ring represents a very important class owing to their biological activities such as antimicrobial, anticancer, antihypertensive, antidiabetic, antimycobacterial and antitubercular properties. Similarly, the bispirooxindole scaffold recently has drawn considerable interests because of its exclusive structural and stereochemical diversity. Only a few examples have been reported till date for enantioselective construction of the pharmaceutically important bispirooxindole architectures. Considering the importance of bispirooxindoles and pyrrolidinyl spirooxindole scaffolds, we were interested in merging them in a single molecular framework. In this chapter, a Michael addition/cyclization cascade reaction between 3-isothiocyanato oxindoles and exocyclic enones for the enantioselective synthesis of 3,2′-pyrrolidinyl bispirooxindole derivatives has been illustrated. With the help of a quinine-derived bifunctional squaramide as the catalyst, this protocol delivers bispirooxindoles bearing three contiguous stereogenic centers, in high yields and generally with outstanding diastereo- and enantioselectivity. Reference: Kayal, S.; Mukherjee, S. manuscript under preparation.

Myo-inositol is ubiquitous in nature and is found at the structural core of a diverse range of biologically important derivatives, including phosphatidylinositols, inositol phosphates and mycothiol. The synthesis of myo-inositol derivatives is notoriously difficult due to the need to control both regio- and enantioselectivity. As a result, synthetic routes to derivatives of this type are often lengthy and low yielding. The first biosynthetic step in the production of all myo-inositol metabolites is the isomerisation of D-glucose 6- phosphate to L-myo-inositol 1-phosphate as mediated by L-myo-inositol 1-phosphate synthase (INO1). For the protozoan parasite Trypanosoma brucei, INO1 is essential for survival and its version of the enzyme (TbINO1) has a high turnover. This makes TbINO1 an attractive candidate for the biocatalytic production of L-myo-inositol 1- phosphate, and a potential starting point for drastically shortened syntheses of important myo-inositol derivatives. The production of L-myo-inositol 1-phosphate by TbINO1 has been optimised to achieve complete conversion in reaction conditions that facilitate product isolation. Due to problems with an in-batch process, the TbINO1 enzyme was immobilised and the process was transferred to a flow system. This has allowed for production of significant quantities of L-myo-inositol 1-phosphate with a high level of purity. L-myo-inositol 1- phosphate obtained from the flow system has been used to prepare mycothiol glycosylation acceptor, 1,2,4,5,6-penta-O-acetyl-D-myo-inositol, in a concise synthesis with a greatly improved yield over the literature.

Au cours de ce travail de nouvelles méthodes pour la formation de liaison C-N ont été développées. Dans la première partie de cette thèse une application de catalyse métal-ligand bifonctionnelle pour la réaction énantiosélective aza-Michael est démontrée. Dans la deuxième partie nous présentons le travail sur les cyclisations, en utilisant des alcaloïdes du quinquina facilement disponibles, comme catalyseurs des plus prometteurs, fournissant des β-amino-acides d’indoline avec jusqu'à 98% ee. Parmi eux, l’hydroquinidine ressort du lot comme étant le catalyseur donnant le meilleur excès énatiomérique. La troisième partie est liée à l'élaboration d'un nouveau processus intermoléculaires de diamination de styrènes, diènes et triènes, utilisant des bis-sulfonylimides comme source d'azote, en combinaison avec le diacétate de iodosobenzène, qui fournit une approche intéressante et efficace de diamines vicinales biologiquement et chimiquement important. La réaction peut être effectuée à température ambiante sans avoir besoin de protection par atmosphère inerte. / The concept of metal-ligand bifunctionality was successfully applied for an enantioselective aza-Michael reaction by employing well-defined ruthenium amido complexes. The catalyst was optimised and the corresponding chiral indoline β-amino acid derivatives were obtained with high enantioselectivities. Next, a straightforward enantioselective bifunctional organocatalytic approach was also developed. Employing hydroquinidine as catalyst the corresponding cyclic products were obtained in excellent enantioselectivities and quantitative yields. These compounds can be selectively deprotected and applied to peptide synthesis. Finally, we have developed unprecedented diamination reactions of styrenes, butadienes and hexatrienes employing easily accessible hypervalent iodine(III) reagents under robust reaction conditions. The first examples of the metal-free 1,2-diamination of butadienes were demonstrated and this oxidation methodology was further extended to the highly attractive 1,4 installation of two nitrogen atoms within a single step.

Au cours des dernières années, l'utilisation des carbènes N-hétérocycliques (NHCs) en tant qu'organocatalyseurs a connu un succès impressionnant. Dans ce manuscrit, nous présentons le design et la synthèse de nouveaux organocatalyseurs NHC bifonctionnels, et leurs applications pour la chimie énantiosélective des homoénolates. En parallèle de ces études, une approche conceptuellement nouvelle aux carbènes de pyridine est proposée et exploitée dans une réaction à trois composants originale. Globalement, ce travail contribue au progrès de la connaissance sur l'utilisation des carbènes comme organocatalyseurs et intermédiaires réactionnels. / N-heterocyclic carbenes (NHCs) have become extremely popular organocatalysts in last decade. In this manuscript, we present our work in the design and the synthesis of a new class of bifunctional NHC organocatalysts, and their applications in enantioselective reactions with homoenolate equivalents. Additionally, a conceptually new synthetic approach to pyrid-2-ylidene carbenes is proposed and used in an original three-component reaction. In a broad sense, this work contributes to the progress of knowledge on the use of NHCs as organocatalysts and reaction intermediates.