This diploma thesis is focused on synthesis of enantiomeric and diastereomeric pure bispirocyclic compounds via sequential Mannich/hydroamination reaction. The first part is focused on the optimization of reaction conditions of enantioselective asymmetric organocatalytic Mannich reaction of pyrazolone derivatives with isatin-derived ketimines. The enantiomerically enriched Mannich adducts were used in hydroamination cyclization. The second part of the work is focused on finding the suitable reaction conditions for performing the Mannich reaction and hydroamination as a sequential reaction leading to bispirocyclic compounds. The application of sequential reaction and selected transformations of bispirocyclic compounds was also performed. Key words Asymmetric synthesis, organocatalysis, Mannich reaction, hydroamination, sequential reaction, bispirocyclic coumpounds.

In the thesis, the development of asymmetric organocatalytic [3+3] sequences for the assembly of aminocyclitols is described. A water-based Wittig reaction was developed in order to produce the key enal-based starting materials, which were otherwise difficult to obtain commercially and synthetically. The enals derived from the Witig reaction were employed in the synthesis of both natural products and synthetic analogs of compounds in the amaryllidaceae family. The [3+3] Michael-aldol sequence described herein provided regio-, diastereoand enantioselective access to the core of the various targeted molecules, containing 3 to 4 defined stereocenters. The sequence was optimized via manipulation of the structures of both the organocatalyst and base used leading to increased selectivity and yield. Complete total synthesis of the natural product (+)-trans-dihydrolycoricidine was achieved using the optimized organocatalytic Michael-aldol sequence. The most effective catalyst/base combination for this synthesis was found to be a comercial diphenylsilylprolinol ether and quinidine, which led to a dramatic reduction in the number of synthetic steps taken to the final product, and highest yield, when compared to other reported approaches: in 9 chemical steps, 12% overall yield and 98% e.e. were achieved. Two non-natural analogues were also synthesized using this methodology in order to probe the minimum pharmacophore of the amaryllidaceae derivatives, as they are known to express anti-viral and anti-cancer activity for certain cell lines. (+)-3- Deoxydihydrolycoricidine containing 4 chiral centers, was synthesized via the same [3+3] Michael-aldol sequence as the natural product in 6 steps with 15% yield and >99% e.e. Similarly, (+)-trans-3-epidihydrolycoricidine was obtained in 6 steps, 27% yield and >99% e.e. The biological activity of these derivatives is yet to be examined. This highly effective method for the preparation of chiral aminocycllitols can be generalized toward the synthesis of numerous targets, which will be the focus of future research. / Thesis / Doctor of Philosophy (PhD)

This thesis is primarily focused on the development of Wittig methodologies and the applications of the product alkenes in organocatalysis and drug discovery. Herein is described an aqueous Wittig methodology for the synthesis of α-methylstilbenes and their use in the preparation of novel triazole stilbene inhibitors of aromatase, a clinically validated target for the treatment of estrogen receptor positive breast cancer. As well, a one-step, stereoselective synthesis of alkenyl phenols was developed. The method provides easy access to a variety of compounds that contain this synthetically and biologically important functionality, including natural product phenolic stilbenes. In turn, alkenyl phenols were used as a key component in a novel organocatalytic methodology for the synthesis of cyclobutanes in good yields and high enantioselectivity. Notably, this is one of relatively few asymmetric, catalytic methods for cyclobutane synthesis. Preliminary biological activity of some of these cyclobutane derivatives is reported, including promising anti-cancer activity. Finally, a ten-step total synthesis of the Amaryllidaceae alkaloid (+)-trans-dihydronarciclasine was completed. The synthesis features an organocatalytic Michael-aldol cascade on a cinnamaldehyde derivative, which was prepared using a Wittig methodology previous reported by the McNulty group. Importantly, this compound was found to be one of the most potent anti-Zika compounds reported to date. Future work should focus on improving the potency and selectivity of the various aforementioned chemotherapeutics, with concurrent efforts to build upon the novel methodologies discussed herein. / Thesis / Doctor of Philosophy (PhD) / The Wittig reaction is one of the best ways to make alkenes, a type of reactive bond between two carbon atoms. A new Wittig reaction was developed and used in the preparation and discovery of potent inhibitors of aromatase, an enzyme responsible for the proliferation of many breast cancers. As well, another Wittig methodology was created for the straightforward synthesis of an otherwise difficult to prepare class of alkenes. In turn, these types of alkenes were used in a novel preparation of cyclobutanes, a chemical structure that is difficult to make but can impart useful properties to drugs and materials. Finally, a Wittig reaction previously reported by the McNulty group was used as part of a chemical synthesis of trans-dihydronarciclasine, a rare natural product isolated from daffodils. Trans-dihydronarciclasine was discovered to have antiviral activity and is one of the most potent inhibitors of the Zika virus discovered to date.

This thesis details investigations into organocatalytic reactions promoted by N Heterocyclic Carbenes (NHCs) that proceed via an assumed azolium enolate intermediate. Initial research focused on the catalytic asymmetric synthesis of β-lactones via an NHC-catalysed formal [2+2] cycloaddition of alkylarylketenes and chloral. This process operated in good yield (typically >70%) and moderate diastereoselectivity (typically ~75:25 dr, anti:syn) for a range of alkylarylketenes. The enantioselectivity was consistently high for the major anti diastereomer (typically >80% ee) and minor syn diastereomer (typically >70% ee). Interestingly, when a ketene bearing a 2 substituent on the aryl ring, or one that included an α-branched alkyl group was used, an exclusive asymmetric chlorination pathway was accessed. This is, to the best of our knowledge, the first use of chloral as an electrophilic chlorination agent. This methodology was found to be applicable to a range of 2-arylsubstituted alkylarylketenes in good yield and enantioselectivity (typically >70% yield and up to 92% ee). The scope of this reaction with respect to the aldehyde moiety was then analysed with 2-nitrobenzaldehyde providing β-lactone products in excellent dr (up to 94:6 syn:anti) and with good yield and enantioselectivity (typically >60% yield and >80% ee). Importantly these β-lactone products were amenable to further derivatisation with transformation to β-amino- and β-hydroxy acids. Following the identification of an NHC-catalysed chlorination reaction using chloral, the development of a general procedure was undertaken. Following a wide screen of electrophilic chlorination sources, 2,3,4,5,6,6 hexachlorocyclohexa 2,4 dienone was identified as optimal, operating in excellent yield (up to 97%) but in moderate to poor levels of enantioselectivity (21−61% ee). Efforts to expand the practicality of azolium enolate processes focused on the use of α-aroyloxyaldehydes as bench stable mono-substituted ketene surrogates. A range of differentially substituted α-aroyloxyaldehydes allowed access to δ-lactones via the NHC-catalysed [4+2] cycloaddition between azolium enolates and β,γ unsaturated α ketoesters. Following initial optimisation the reaction proceeded in exquisite diastereo- and enantiocontrol (typically >95:5 dr and >99% ee).

No description available.

Depuis des dizaines d’années, les chimistes organiciens ont accru leurs capacités à synthétiser des molécules complexes de manière exponentielle par le développement de nouvelles méthodes toujours plus élaborées. Malgré ces accomplissements, le challenge de synthétiser de nouvelles molécules toujours plus complexes de manière sélective et efficace reste toujours d’actualité. Dans le premier chapitre, nous introduirons la notion de chiralité de manière générale. Ensuite, les différentes stratégies pour contrôler la chiralité en synthèse organique seront exposées, en se focalisant plus particulièrement sur l’organocatalyse énantiosélective. Ensuite, dans le deuxième et troisième chapitre, le contrôle de la chiralité centrale sera étudié d’une part dans une synthèse de tetrahydropyranes et d’autre part dans l’addition de Michael impliquant les 1,3-cetoamides α,β-insaturés. Dans le quatrième chapitre, d’autres types de chiralité moins conventionnelles seront examinées. Tout d’abord, une étude portant sur la racemization des furanes atropisomères sera menée. Ensuite, des stratégie innovantes seront mises en œuvre pour la synthèse [4]- et [5] helicènes via notamment des phénomènes de conversion de chiralité. / In the last century, the ability of organic chemists to build complex molecules has grown exponentially. Despite these achievements, the challenge of synthesizing new molecules efficiently and selectively remains open. In the first chapter, we will discuss the definition of chirality as a transversal topic in science. Subsequently we will discuss the different strategies to control chirality in organic synthesis, with a special attention to organocatalysis. In the second and third chapter we will focus on the attempt to control central chirality for the synthesis of substituted tetrahydropyrans and the investigation of the reactivity of α,β-unsaturated 1,3-ketoamides in Michael addition. In the fourth chapter, other less conventional types of chirality will be examined. First, a study on the racemization of atropisomer furans will be conducted. Then, innovative strategies will be implemented for the synthesis [4] - and [5] helicenes via, in particular, chirality conversion approaches.

Jusqu’à très récemment, les catalyseurs pour la synthèse asymétrique étaient limités aux enzymes et aux complexes de coordination. Depuis les années 2000, une troisième approche a vu le jour: l’organocatalyse asymétrique. Il est assez surprenant de constater que parmi la multitude de catalyseurs organiques développés chaque année, une minorité d’entre eux seulement est basée sur de nouveaux squelettes chiraux. En effet, l’introduction d’une nouvelle entité chirale pourrait mener à la découverte de nouvelles combinaisons de substrats ainsi qu’à de nouvelles réactions catalytiques hautement stéréosélectives. C’est pourquoi, nous nous sommes proposé de préparer une série de nouveaux catalyseurs organiques bifonctionnels incluant des fonctions thiourées et basée sur le squelette chiral de la base de Tröger. L’accès aux dérivés énantiopures de la base de Tröger reste un défi majeur. C’est pourquoi, nous avons décidé de mettre au point une méthode efficace et prévisible, pour la résolution des analogues de la base de Tröger. Dans la mesure où l’élaboration d’une telle méthode nécessite un grand nombre de molécules, nous avons synthétisé une série de dérivés de la base de Tröger. La condensation d’anilines variablement substituées avec du paraformaldehyde dans de l’acide trifluoroacétique a été étudiée, conduisant à la synthèse d’analogues symétriques de la base de Tröger. L’utilisation de paraformaldehyde n’étant pas compatible avec tous les groupements fonctionnels, d’autres voies de synthèse ont également été explorées. Ainsi, des dérivés amino et cyano ont été préparés par l’intermédiaire de réactions organométalliques. Ensuite, une voie de synthèse menant aux analogues non-symétriques de la base de Tröger a été mise au point. Finalement, une série de dérivés présentant un pont –NCH2CH2N- a été préparée. La résolution de l’ensemble des composés a été systématiquement étudiée par chromatographie sur la phase stationnaire chirale commerciale Whelk O1. Des relations structure vs. énantioséléctivité ont pu être établies permettant de prédire la séparation par notre méthode. Une corrélation entre l’ordre d’élution et la configuration absolue a également pu être mise en évidence. Enfin, l’activité catalytique des dérivés thiourées de la base de Tröger a été évaluée dans la réaction d’addition de Michael de différents dérivés de l’acide malonique au trans-nitrostyrene. Compte tenu de la faible basicité de la base de Tröger, il a été démontré que l’issue de la réaction est fortement dépendante du pKa du nucléophile. De plus, aucune stéréosélectivité n’a pu être mise en évidence dans cette réaction d’addition.

Protected DHA units, known as dioxanones, are interesting compound which can be used as the building blocks for synthesis of polyoxygenated natural products. The direct aldol reaction is employed for converting of those inexpensive starting materials into enantioenriched products of complexed structures. The stereocontrol in the first aldol reaction is achieved by using organocatalysis. Second aldol reaction is conducted by lithium enolate chemistry leading to anticisanti aldols as a major isomer. On the other hand boron chemistry provides antitransanti products. This strategy is used for synthesis of higher sugars.

This work covers recent advances in the Stetter reaction, including two novel domino Stetter reactions and preliminary studies on quaternary center formation via the intermolecular Stetter reaction. The N-heterocyclic carbene (NHC) catalyzed domino Stetter-aldol-Michael dimerization of o-formyl chalcone derivatives 36 affords spiro bis-indane homo-dimers 38 in good yields and moderate to high diastereomeric ratios. Three carbon-carbon bonds, including the hindered quaternary center at the spiro ring junction, form at a remarkable rate under mild reaction conditions. Spiro bis-indanes 39 are also produced in moderate to good yields through the Stetter-aldol-aldol reactions of o-formyl chalcones 36 with phthalaldehyde derivatives 27. The scope, limitations, and potential applications of these remarkable complexity-generating domino reactions are discussed. Preliminary results in the formation of quaternary centers via the intermolecular Stetter reaction are also disclosed. The viability of β,β-disubstitued Meldrum’s acid, diethyl malonate, and malononitrile alkylidenes as well as diphenylcyclopropenone and 3-phenylcyclobutenone as acceptors in the Stetter reaction are discussed.

Protected DHA units, known as dioxanones, are interesting compound which can be used as the building blocks for synthesis of polyoxygenated natural products. The direct aldol reaction is employed for converting of those inexpensive starting materials into enantioenriched products of complexed structures. The stereocontrol in the first aldol reaction is achieved by using organocatalysis. Second aldol reaction is conducted by lithium enolate chemistry leading to anticisanti aldols as a major isomer. On the other hand boron chemistry provides antitransanti products. This strategy is used for synthesis of higher sugars.