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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.

The thesis entitled “Studies on the Ring-opening Reactions of Vinylcyclopropanes, Vinylcyclobutanes, and other Small-ring Systems” is divided into four chapters. Chapter 1: Part A: Bromenium Catalyzed Tandem Ring-opening/Cyclization of Vinylcyclopropanes and Vinylcyclobutanes: A [3+2+1]/[4+2+1] Cascade for the Synthesis of Chiral Amidines. In this part of the Chapter, we discuss our serendipitous results in the reaction of vinylcyclopropanes (VCPs), like Δ2-carene under Sharpless aziridination conditions using chloramine-T and phenyltrimethylammonium tribromide (PTAB) as catalyst in acetonitrile. The reaction follows a [3+2+1] cascade pathway involving acetonitrile (Ritter-type reaction) to give chiral bicyclic amidines in very good yield. The reaction was found to be tolerant to hydroxyl- and keto-functionalities. . existence of a tight-carbocation intermediate. Our attempts to access bridged bicyclic amidines from vinylcyclobutanes like α-pinene resulted in the formation of bicyclo[4.3.1]pyrimidines successfully in moderate yields. Partial racemization of the product was observed and this observation was rationalized through competing cyclization pathways. Vinylcyclopropanes and Vinylcyclobutanes towards the Synthesis of Chiral Amidines. In this part of the chapter, we discuss our computational results obtained from modeling the reaction pathway in gas-phase and solvent dielectrics (acetonitrile). Initially, we modeled the ring-opening process, to visualize the geometrical features and the orbital interactions present in the tight-carbocation intermediate. We also modeled the competing cyclization pathways to justify the racemization observed in the case of α-pinene. Our calculations show that, the free energy of activation for the allylic substitution and the direct substitution pathways are nearly equal. Thus, the formation of both the enantiomers is feasible kinetically. the proposed cascade pathway. Chapter 2: Electrophile-Induced Indirect Activation of C-C Bond of Vinylcyclopropanes: A Masked Donor-Acceptor Strategy for the Synthesis of Z-Alkylidenetetrahydrofurans. In Chapter 2, we discuss the results of introducing VCPs as masked donor-acceptor systems under electrophilic conditions. Our aim was to activate the VCPs with in situ generated bromine electrophile to give a tight-carbocation as discussed in Chapter 1. Further, the tight-carbocation can be used to access novel heterocycles. formation of Z-alkylidienetetrahydrofurans with high stereoselectivity across the exocyclic double bond. An interesting reactivity of benzofuran derived VCPs was observed, where the ring-opening occurred concurrently adjacent to the heteroatom and at the benzylic position to give both cis- and trans-furofuran. methyl group on VCP as a chiral marker. Under our standard reaction conditions, cyclization resulted in the retention of configuration at the phenyl center. The retention of configuration results through a directed attack of hydroxyl group on the tight-carbocation. functionalized tetrahydrofurans Chapter 3: σ-Ferrier Rearrangement of Carbohydrate Derived Vinylcyclopropanes: A Facile Approach to Oxepane Analogs In the present chapter, we have presented the idea of a tight-carbocation through an electrophile-mediated activation of VCPs on carbohydrate derived VCPs through a σ-Ferrier rearrangement. We expected high stereoselectivity at the anomeric center assuming the existence of a tight carbocation intermediate. Reaction of glucose-derived VCPs resulted in the ring-expansion to oxepane analogues, but with poor diastereoselectivity. Similar selectivity was observed even in the case of galacto- derived VCPs. intermediate. The planar oxonium intermediate is a more stable intermediate but reacts with poor facial selectivity. With water as nucleophile, the reaction led to a diene aldehyde through a complete ring-opening of the oxepane formed, followed by the elimination of hydrogen bromide. the unsaturated oxepanes with facial diastereoselectivity. Chapter 4: One-Pot Synthesis of β-Amino/β-Hydroxyselenides and Sulfides from Aziridines and Epoxides. In this chapter, we present details of the reductive cleavage of aromatic disulfide and diselenide bonds mediated by Rongalite. The reagent reacts with disulfides to generate thiolate anion through a two-electron transfer mechanism. The thiolate anion was further utilized for nucleophile-mediated ring-opening of small-ring systems. The reaction of aziridines with aryl disulfides mediated by Rongalite, resulted in regioselective ring-opening to from β-aminosulfides. In the case of trisubstituted aziridines, the reaction led to a regioisomeric mixture of products. The reaction was found to be efficient for the ring-opening of epoxides as well. diselenides and Rongalite, successfully underwent cleavage of diselenide bond followed by ring-opening to give β-aminoselenides. The reaction was successful with epoxides as starting material to yield β-hydroxyselenides

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Over the past decades, functional group manipulation of aromatic precursors has been a common strategy to access new aromatic compounds. However, these classical methods, such as Friedel-Crafts alkylations and electrophilic/nucleophilic aromatic substitutions, have shown lack of regioselectivity besides the use of activators in excess amounts. To this end, numerous benzannulations to form benzo-fused substrates via Diels-Alder (DA), ring-closing metathesis (RCM), cycloaddition, and transition-metal-promoted processes have been reported. Appending a benzene ring directly onto a pre-existing ring is preferable to many classical methods due to the likely reduction of reaction steps and superior regiocontrol. However, many of these benzannulation reactions require air- and/or moisture- sensitive reaction conditions, a last oxidation step, or the use of highly functionalized precursors. Here we disclose three ‘complementary’ intramolecular ring-opening benzannulations to access a large array of functionalized (hetero)aromatic scaffolds utilizing cyclopropenes-3,3-dicarbonyls, alkylidene cyclopropanes-1,1-diesters, and 2,3-dihydrofuran O,O- and N,O- acetals as building blocks. More than 70 benzo-fused aromatic compounds were synthesized using this complementary approach with yields up to 98% and low catalyst loadings. With these benzannulation reactions in hand, we aim to open the synthetic door to a handful of bioactive natural products.

Modeling the competition between drying and curing processes in polymerizing films is of great importance to many existing and developing materials synthesis processes. These processes involve multiple length and time scales ranging from molecular to macroscopic, and are challenging to fully model in situations where the polymerization is non-ideal, such as sol-gel silica thin film formation. A comprehensive model of sol-gel silica film formation should link macroscopic flow and drying (controlled by process parameters) to film microstructure (which dictates the properties of the films). This dissertation describes a multiscale model in which dynamic Monte Carlo (DMC) polymerization simulations are coupled to a continuum model of drying. Unlike statistical methods, DMC simulations track the entire molecular structure distribution to allow the calculation not only of molecular weight but also of cycle ranks and topological indices related to molecular size and shape. The entire DMC simulation (containing 106 monomers) is treated as a particle of sol whose position and composition are tracked in the continuum mass transport model of drying. The validity of the multiscale model is verified by the good agreement of the conversion evolution of DMC and continuum simulations for ideal polycondensation and first shell substitution effect (FSSE) cases. Because our model allows cyclic and cage-like siloxanes to form, it is better able to predict the silica gelation conversion than other reported kinetic models. By studying the competition between molecular growth and cyclization, and the competition between mass transfer (drying) and reaction (gelation) on the drying process of the sol-gel silica film, we observe that cyclization delays gelation, shrinks the molecular size, increases the likelihood of skin formation, and leads to a molecular structure gradient inside the film. We also find that compared with a model with only 3-membered rings, the molecular structure is more complicated and the structure gradients in the films are larger with 4- membered rings. We expect that our simulation will allow better prediction of the formation of structure gradients in sol-gel derived ceramics and other nonideal multifunctional polycondensation products, and that this will help in developing procedures to reduce coating defects.

La partie principale de ce manuscrit traite du développement de nouvelles méthodologies utilisant la substitution propargylique catalysée par des sels de fer(III), pour la formation de divers hétérocycles azotés (∆4-isoxazolines, isoxazoles, cis-acylaziridines et pyrimidines). En premier lieu, de nouvelles synthèses monotopes de ∆4-isoxazolines et d'isoxazoles diversement substitués impliquant des réactions de cyclisation catalysées par diverses espèces carbophiles ([Au], [Pd], [I+]) ont été développées. La fragilité de la liaison N-O des ∆4-isoxazolines a pu être ensuite exploitée pour conduire à la formation de cis-acylaziridines. De nouvelles voies d'accès aux (Z)-β-énaminones et aux pyrimidines trisubstituées ont été également développées. / The main part of this manuscript deals with the development of new methodologies using iron(III)-catalyzed propargylic substitution, for the synthesis of various nitrogen-containing heterocycles (Δ4-isoxazolines, isoxazoles, cis-acylaziridines and pyrimidines). Firstly, new one-pot syntheses of variously substituted Δ4-isoxazolines and isoxazoles involving cyclization reactions promoted by various carbophilic species ([Au], [Pd], [I+]) have been developed. The weakness of the Δ4-isoxazoline N-O bond has been then exploited, leading to the formation of cis-acylaziridines. New pathways to (Z)-β-enaminones and trisubstituted pyrimidines have also been developed.

Les dérivés hétérocycliques sont incorporés dans la structure de nombreuses molécules biologiquement actives, naturelles ou de synthèse. Ce travail de thèse décrit les efforts réalisés pour développer de nouvelles voies d'accès à deux familles de ces composés hétérocycliques : les hétérocycles phosphorés et les pyrimidines. Le premier chapitre est dédié à une étude bibliographique de l'ensemble des méthodologies d'hydrophosphonylation et d'hydrophosphinylation connues à ce jour. Le second chapitre décrit nos efforts pour développer des réactions de formation de liaisons carbone-phosphore pallado-catalysées. Le dernier chapitre est consacré à la mise au point d'une synthèse originales de β-enaminones protégées et de leur utilisation pour la synthèse de pyrimidines diversement substituées. / Compounds classified as heterocyclic are found in numerous natural products and molecules biogically active. The work described herein will focus on the synthesis of two families of heterocyclic compounds through two distincts synthetic pathways. The first one lays in the organophosphorus chemistry. In Chapter I, numerous methodologies known in the literature will be explained. The significance of metal-catalyzed hydrophosphonylation / hydrophosphinylation reactions will be described. Chapter II stands for the experimental exploration of metal-catalyzed intramolecular and intermolecular P-C bond formation. In Chapter III the attention will be turned to the development of a base-catalyzed synthesis of Cbz-protected β-enaminones and their subsequent implementation in the cyclization reaction towards 2,4,6-trisubstituted pyrimidines.

Na primeira parte da tese são apresentados os resultados referentes aos estudos mecanísticos da reação de ciclização de álcoois homoalílicos com o sistema iodo/iodo(III). Os experimentos demonstraram que essa reação ocorre pela intermediação de espécies eletrofílicas hipoiodídicas e que apenas um intermediário acíclico contribui efetivamente para a formação do produto desejado. Na segunda parte da tese são discutidos os resultados obtidos na ciclização com iodo/iodo(III) para uma série de substratos insaturados. Essa metodologia mostrou-se versátil, permitindo que uma grande variedade de derivados tetra-hidrofurânicos metóxi-substituídos pudessem ser obtidos a partir de álcoois primários e secundários. Em todas as reações uma mistura de diastereoisômeros cis/trans foi obtida em rendimentos moderados. Aplicando-se esse método a 4-alquenóis e ácidos carboxílicos insaturados, apenas produtos análogos aos obtidos em protocolos clássicos de ciclização eletrofílica puderam ser acessados. Nesses casos, devido a uma limitação dos substratos, a ciclização ocorre exclusivamente pelo ataque intramolecular da hidroxila/carboxila levando à formação do anel de cinco membros. Submetendo sulfonamidas homoalílicas ao sistema iodo/iodo(III) produtos de coiodação foram isolados. Pirrolidinas metóxi-substituídas foram obtidas empregando-se t-BuOK como base para promover a ciclização. Esse método se mostrou efetivo no caso de substratos suscetíveis à migração, contendo grupos arila na ligação dupla e também foi aplicado com sucesso para os álcoois homoalílicos primários e secundários, o que permitiu obter em alguns casos os tetra-hidrofuranos em rendimentos maiores do que no método convencional. / In the first part of the thesis are presented the results regarding the mechanistic studies of the cyclization reaction of homoalyl alcohols with the iodine/iodine(III) system. The experiments demonstrated that this reaction occurs through the intermediation of hypoiodidic electrophilic species and that only an acyclic intermediate effectively contributes to the formation of the desired product. In the second part of the thesis the results obtained in the cyclization with iodine/iodine(III) for a series of unsaturated substrates are discussed. This methodology proved to be versatile, allowing a large variety of methoxy-substituted tetrahydrofuran derivatives to be obtained from primary and secondary alcohols. In all reactions a mixture of cis/trans diastereoisomers was obtained in moderate yields. Applying this method to 4-alkenols and unsaturated carboxylic acids, only products analogous to those obtained in classical electrophilic cyclization protocols could be accessed. In these cases, due to a limitation of the substrates, the cyclization occurs exclusively by the intramolecular hydroxyl/carboxyl attack leading to the formation of the five-membered ring. Subjecting homoalyl sulfonamides to the iodine/iodine(III) system co-iodination products were isolated. Methoxy-substituted pyrrolidines were obtained using t-BuOK as a base to promote cyclization. This method proved to be effective in the case of substrates susceptible to migration, containing aryl groups in the double bond and was also successfully applied to the primary and secondary homoalyl alcohols, which in some cases allowed the tetrahydrofurans to be obtained in higher yields than in the conventional method.