Universiẗat-Gesamthochsch., Diss.--Paderborn, 1996.

Since its discovery in 1912, the Mannich reaction has been widely utilized in organic chemistry to form C-C bonds. Reactivity of an enol with an imine allows for easy formation of a [beta]-aminoketone. Enamines have also been widely utilized as convenient nucleophiles. In our work, unexpected reactivity of the [gamma] position of [beta]-enamidoesters in a Brønsted acid environment and high enantioselectivity of a Mannich reaction were achieved through chiral phosphoramidic acid catalysis. A novel class of chiral phosphoramidic acids was designed, synthesized from the corresponding diamines, with several sulfonyl N-protecting groups, and characterized. Their unique properties arise from their Brønsted acid nature, atropisomerism and ability to form complexes via H-bond. Once prepared, such catalysts were successfully used as organocatalysts for the regio- and enantioselective Mannich reaction of [beta]-enamidoesters and imines. Their activity is described as a method to reverse the regioselectivity of the nucleophile while achieving high enantioselectivities in the formation of chiral benzhydrils. A diverse range of imines has been tested, obtaining yields of up to 93% and enantioselectivities of up to 99:1. A few substituted enamines were also tested to study the influence of substituents on the regioselectivity. A mechanism for this reaction is proposed and kinetic studies confirmed that the reaction is first order in catalyst. The ozonolysis of the product of this Mannich reaction was performed to prove the absolute stereochemistry of the product; and a new efficient methodology for the asymmetric preparation of aminoacid [beta]-phenyl-[beta]-alanine benzyl ester is described. The reduction of the enamide moiety of the Mannich product was attempted via asymmetric hydrogenation and via hydride reduction to diastereomerically obtain 1,3-diamines, which are compounds of major synthetic interest. Unfortunately our attempts in this direction were not successful. Finally, a multicomponent reaction between an aldehyde, a substituted phenol, and a styrylboronate was developed as an alternative method for the preparation of chiral benzhydrils. This process is also organocatalytic and the methodology was optimized in the presence of 3-3'-disubstituted BINOLs. Yields up to 71% and enantioselectivities up to 96:4 were achieved. A mechanism for this organocatalytic reaction is also proposed.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第19518号 / 理博第4178号 / 新制||理||1600(附属図書館) / 32554 / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 時任 宣博, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Nous avons mis en évidence l'efficacité des sels de bismuth(III) comme catalyseurs de la réaction de Mannich. Nous avons d'abord étudié la version à trois composantes de la réaction de Mannich dans laquelle réagissent un aldéhyde, une aminé et un énolate silylé. Parmi les différents sels de bismuth(III) étudiés, le triflate de bismuth s'est montré particulièrement efficace. Une vaste gamme de p-aminocétones et de P-aminoesters ont été préparés par cette méthode dans des conditions réactionnelles douces avec une faible charge catalytique (1-2 mol % du sel de bismuth(HI)). Nous avons également rapporté la première version catalytique de la réaction de Mannich entre des A/-alkoxycarbonylaminosulfones et des énolates silylés. La méthode développée tire parti de conditions réactionnelles douces et d'un processus hautement catalytique. En effet, seulement 0,5 mol % de triflate de bismuth est nécessaire pour une catalyse efficace de la réaction. Cette version de la réaction de Mannich permet d'obtenir des composés Paminocarbonylés protégés par un groupement Cbz. Plus récemment, nous avons montré que le triflate de bismuth catalyse la réaction de Mannich à trois composantes dans l'eau, comme alternative aux solvants organiques classiques. Nous avons développé une réaction dans laquelle les éthers d'énols silylés habituels ont été remplacés par les cétones correspondantes, éliminant ainsi une étape de synthèse. Cette réaction de Mannich en conditions directes s'inscrit particulièrement bien dans la philosophie d'économie d'atomes et de respect de l'environnement. Nous avons également étudié la réaction d'homoMannich, qui consiste en l'addition d'un homoénolate sur une imine. Des acétals silylés de cyclopropanones, qui sont des précurseurs d'homoénolates, sont mis en réaction avec différentes imines en présence d'un sel de bismuth(III) pour conduire aux y-aminoesters correspondants avec de bons rendements. La méthodologie développée au laboratoire a aussi été appliquée à une tentative de synthèse totale de la (±)-pumiliotoxine C. Cet alcaloïde naturel comporte un système bicyclique de type décahydroquinoline qui peut être élaboré à partir d'une réaction de Mannich. Finalement, la synthèse énantiosélective de composés p et y-aminocarbonylés via des sels de bismuth chiraux a été explorée. Nous avons étudié les réactions de Mannich et d'homo-Mannich avec différents ligands chiraux de type diol en solvant organique ainsi qu'en conditions aqueuses. / We evidenced the efficiency of bismtuh(III) salts as catalysts in the Marinich reaction. We first investigated the one-pot version of this reaction in which an aldehyde, an amine and a silyl enol ether were reacted together. Among the various bismuth(III) salts investigated, bismuth triflate proved to be very effective. A large array of P-amino ketones and P-amino esters were prepared under mild reaction conditions, and with low catalyst loading (1-2 mol % of bismuth(HI) salt). We also reported the first catalytic Mannich reaction of TV-alkoxycarbonylaminosulfones with silyl enolates. As an improvement over other methods, mild reaction conditions and highly catalytic process are reached. Indeed, 0.5 mol % bismuth triflate efficiently catalyzes this reaction. The described method allows a quick access to Cbz-protected (3-amino carbonyl compounds. More recently, we shown that bismuth triflate catalyzes the one-pot Mannich reaction using water as an alternative to classical organic solvents. In this reaction, the silyl enol ethers were replaced by the corresponding ketones, decreasing the number of synthetic steps. This direct Mannich reaction is particularly interesting from an atom economy viewpoint and has the advantage to use water as an environmentally benign solvent. We also studied the homo-Mannich reaction, which involves the addition of a homoenolate to an imine. Cyclopropanone silyl acetals, which are homoenolate precursors, were reacted with various imines in the presence of bismuth(III) salts to afford the corresponding y-amino esters in good yields. Our methodology was tentatively applied to the total synthesis of (±)-pumiliotoxin C. This natural alkaloid contains a decahydroquinolin core structure, which can be elaborated from a Mannich reaction. Finally, enantioselective synthesis of |3 and y-amino carbonyl compounds via chiral bismuth(III) salts was examined. We studied both the Mannich and homo-Mannich reactions with different diol-derived chiral ligands in organic solvents as well as under aqueous conditions.

L’objectif de cette thèse était d’accéder au squelette de deux grandes familles d’alcaloïdes, les aspidosperma et les morphinanes, avec pour but, l’utilisation de précurseurs communs, les arylcyclohexa-2,5-diènes. Dans un premier temps, ces arylcyclohexa-2,5-diènes, obtenus par réaction de Birch alkylante, ont été désymétrisés par application de la réaction de Michael. Les substrats ainsi obtenus ont été diversement fonctionnalisés jusqu’à obtention du squelette pentacyclique des aspidosperma. Dans un second temps, plusieurs méthodologies utilisant des réactions de type Mannich ont été développées. Ces méthodologies ont permis d’atteindre une base tricyclique de la famille des morphinanes. Plusieurs transformations ont ensuite été examinées afin d’accéder au squelette tétracyclique avancé de cette famille d’alcaloïdes. / The objective of this work was to access the skeleton of two families of alkaloids, the aspidosperma and the morphinan, using arylcyclohexa-2,5-dienes as common synthetic precursors. In one hand, these arylcyclohexadienes, synthesized by reductive Birch alkylation, were desymmetrized via the Michael reaction. The resulting compounds were then functionalized to give the pentacyclic skeleton of aspidosperma alkaloids. On the other hand, several methodologies were developed using Mannich type reactions. These methodologies allowed an access to the tricyclic framework of the morphinan family. Several transformations were then examined to attain the tetracyclic skeleton of this family of alkaloids.

Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient cyclobutane. The novel tandem intramolecular photocycloaddition- retro-Mannich (TIPCARM) sequence leads to a spiropyrrolidine which is poised to undergo a second retro-Mannich fragmentation [TIPCA(RM)₂] that expels the malonate unit present in the photo substrate and generates transiently an indolenine. The indolenine undergoes rearrangement to a β-carboline which can undergo further rearrangement under oxidizing conditions to an oxindole. Three oxindole natural products, coerulescine, horsfiline and elacomine, were synthesized using this strategy. The TIPCARM strategy was extended to an approach that would encompass the Vinca alkaloids vindorosine and minovine. In this case, the TIPCARM sequence was followed by an intramolecular cyclization that provided tetracyclic ketone 5.86 containing rings A, B, C and D of vindorosine. A tetracyclic intermediate was synthesized which could also provided access to the Vinca alkaloid minovine. / Graduation date: 2012

Sur la base de travaux précédemment réalisés au laboratoire concernant la réaction de Mannich vinylogue (RMV), nous avons continué le développement de cette réaction en mettant au point un protocole multi-composants. Nous avons ensuite étendu la gamme des substrats compatibles à différents hétérocycles azotés, de nouveaux électrophiles et nucléophiles avec des rendements généralement supérieurs à 80% et des rapports diastéréomériques supérieurs à 80/20. L’obtention de nombreux clichés de diffraction des rayons X a permis de confirmer que le diastéréomère majoritaire est toujours de configuration relative R*,R*. Nous avons ensuite valorisé ces produits en obtenant, en une étape, des structures tétracycliques complexes. Ces produits ont été synthétisés avec des rendements allant jusqu’à 87% et un rapport diastéréomérique supérieur à 95/5. Une étude de modélisation moléculaire a permis d’apporter une explication à cette diastéréosélectivité. La séquence RMV / cyclisation a conduit à la formation contrôlée de quatre centres stéréogéniques contigus. Ces structures tétracycliques ont ensuite servi de produits de départ vers la synthèse d’analogues d’une molécule naturelle antitumorale : l’émétine. Les intermédiaires de synthèse ont été testés pour leur activité cytotoxique. / On the basis of previous work done in the laboratory on the vinylogous Mannich reaction, we pursued the development of this reaction by devising a three component procedure. We then extended the scope of the reaction to different aza-heterocycles, to new electrophiles and nucleophiles with yields generally over 80% and diastereomeric ratios over 80/20. The numerous X ray structures obtained confirmed that the major diastereomer always present an R*,R* configuration. These substrates were then used to prepare complex tetracyclic structures in one step. These products were obtained with yield up to 87% and diastereomeric ratios up to 95/5. This diastereoselectivity was rationalized using molecular modeling. This vinylogous Mannich / cyclization reaction sequence allowed the controlled formation of four contiguous stereogenic centers. These tetracyclic structures were then used as starting points for the synthesis of analogues of emetine, a natural antitumor compound. The synthetic intermediates were tested for their cytotoxic activity.

Pyrrolidine and pyrrolidinone rings are common motifs found in many biologically active natural products and drugs. Accordingly, our work focuses on the development of new methodologies for their one-pot synthesis. An efficient diastereoselective nitro-Mannich / lactamisation reaction cascade of methyl 3-nitropropanoate with cyclic and acyclic imines for the direct preparation of trans-monocyclic and fused tricyclic pyrrolidinone derivatives was developed. The reaction is easy to perform, broad in scope and tolerates a wide variety of functional groups. For the monocyclic methodology, 28 examples with a very good average yield of 72% and excellent diastereocontrol (typical dr >98:2) were obtained using optimized conditions and varying the amine and the aldehyde reagents. The methodology has been extended to the synthesis of 1,3,5-trisubstituted 4-nitropyrrolidinone derivatives using α-substituted 3-nitropropanoate. Using a one-pot protocol, 22 derivatives were synthesised in good yields (65% average) and diastereomeric ratios ranging from 3:1 to 30:1 in favor of the trans/trans diastereoisomer. In addition, the nitro-Mannich / lactamisation cascade of methyl 3-nitropropanoate was developed further to allow the rapid synthesis of 5-isopropyl-4-nitropyrrolidin-2-one from reaction with ammonium acetate and 1-butyl-4-nitropyrrolidin-2-one from reaction with formaldehyde. Also, the synthetic utility of the nitro-pyrrolidinones formed was exemplified through various functional group modifications: the selective reduction of the lactam carbonyl, the reduction of the nitro group in the presence or absence of a carbonyl group and the reductive removal of the nitro group. The development of an enantioselective version of the cascade under chiral Brönsted acid catalysis provided promising results (up to 90% ee). Moreover, various studies were undertaken to understand the mechanism of the reaction and the nitro-Mannich / latamisation cascade is now well understood. Furthermore, a formal synthesis of rac-Slaframine in 8 steps and 15% overall yield was achieved and it inspired additional work towards a nitro-Mannich / epoxide ring opening cascade.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

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