Le motif allyle est présent dans nombreuses molécules naturelles ou d'intérêt biologique et les réactions de substitution allylique sont les transformations les plus utiles pour l'introduction de tel motif dans les molécules cibles. Cette thèse en cotutelle porte sur l'étude de deux aspects de la réaction d'allylation. La première partie de ce travail, réalisée à l'Université de Tunis El Manar, porte sur le développement d'une nouvelle réaction de S-allylation, tandis que la deuxième partie, réalisée à l'UPMC, est dédiée à l'étude d'une réaction d'allylation palladocatalysée inédite. Le premier chapitre, d'introduction bibliographique, décrit l'état de l'art de la réaction de substitution allylique, déclinée selon la nature du nucléophile utilisé : carboné, azoté, oxygéné, ou encore soufré. Le deuxième chapitre décrit le travail expérimental réalisé au laboratoire, qui a amené au développement d'une réaction de S-allylation sur des acétates cycliques de type Morita-Baylis-Hillman. Le troisième chapitre porte sur l'allylation d'énamines palladocatalysée. Une introduction bibliographique initiale montre les caractéristiques de cette transformation, ainsi qu'une sélection d'exemples reportés en littérature, qui génèrent des produits C-allylés où l'azote énaminique est perdu. La suite du chapitre montre le travail accompli afin de développer un nouveau type de C-allylation d'énamines aza-conservateur. Cette nouvelle transformation a été d'abord conçue, puis accomplie expérimentalement, utilisant des énaminones et des conditions réactionnelles spécifiques. / The allyl pattern is present in many natural products and moleculesof biological interest and the allylic substitution reaction is the most useful transformation for the introduction of such motif in the target molécules...

Les réactions permettant la création de liaisons carbone-carbone sont des outils essentiels dans le domaine de la synthèse organique. Elles permettent d'accéder à des structures de plus en plus complexes. Cependant le contrôle de ces réactions en utilisant des partenaires hautement fonctionnalisés reste un enjeu majeur.Le développement de nouvelles méthodologies de synthèse basées sur la réactivité des acrylamides chiraux dérivés d'acides aminés est étudié dans ces travaux. Une nouvelle version de la réaction d'alkylation de pyrroles de type Friedel-Crafts a été développée en utilisant le caractère électrophile d'acrylamides chiraux hautement fonctionnalisés. Le pyrrole peut être monoalkylé ou dialkylé de façon sélective conduisant à de nouvelles structures hétérocycliques portant des enchaînements peptidiques pouvant contenir jusqu'à quatre résidus d'acides aminés. Les acrylamides chiraux portant un motif allyltriméthylsilane conjugué ont été utilisés comme nouveaux réactifs permettant des réactions d'allylation hautement diastéréosélectives et chimiospécifiques vis-à-vis d'aldéhydes. L'extension de cette méthodologie aux aldéhydes α- aminés a été réalisée et permet un accès aisé à des structures analogues des acides γ-aminés. / Reactions allowing carbon-carbon bond creation are essential tools in the field of organic synthesis. These reactions are used to access to more and more complex structures. However their control in the case of highly functionnalized partners is still a serious concern.Development of new methodologies based on the reactivity of aminoacid derivating chiral acrylamides is reported. A new version of pyrrole alkylation reaction was developed using the electrophilic behaviour of highly functionnalized chiral acrylamides. Pyrrole can be selectivly monoalkylated or dialkylated leading to new heterocyclic structures bearing peptidic sequences containing up to four aminoacids residues. Chiral acrylamides bearing a conjuguated allyltrimethylsilane moiety have been used as new reagent in highly diastereoselective and chemospecific towards aldehydes allylation reactions. This methodology was extended to α-aminoaldehydes allowing easy access to γ-aminoacidsanalogues.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thesis advisor: James P. Morken / This dissertation describes the development of two enantioselective methods of carbon-carbon bond formation. Chapter one discusses the development of an enantioselective Pd(0)-catalyzed conjugate addition of allylboronic acid pinacol ester to α,β-unsaturated methylidene ketones. Utilizing the same rationale for regio- and enantiocontrol as in the related enantioselective conjugate allylation of arylidene ketones, this method addresses the gap in technology by expanding the scope of the reaction to include alkyl-substituted enones. Chapter two examines the coupling of allyl electrophiles and allyl metal reagents. With computational insight into the reaction mechanism, a catalyst system was designed to control regioselectivity and enantioselectivity. Isotope labeling studies were carried out to probe the mechanism of the transformation. The reaction also proves to be diastereoselective when a substituted allyl boron reagent is employed. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / Platinum-catalyzed enantioselective diboration of various hydrocarbon starting materials to form stereodefined carbon-boron bonds is reported. The asymmetric Pt-catalyzed 1,4-diboration of <italic>trans</italic>-1,3-dienes provided 1,4-bis(boronate)esters in up to 98:2 er, representing the first enantioselective diene diboration. The enantioselective 1,2-diboration of <italic>cis</italic>-1,3-dienes and 4,4-disubstituted dienes afforded 1,2-bis(boronate)esters in up to 98:2 er. The intermediate allylboronates were utilized in aldehyde allylations to furnish polypropionate-like compounds and stereodefined carbon quaternary centers. The development of a Pt-catalyzed enantioselective diboration of terminal olefins is disclosed, giving the corresponding 1,2-diols in up to 97:3 er. Further optimization and expansion of the scope of this method is also discussed. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Carbonyl allylation and propargylation reactions have been an important tool for the stereocontrolled formation of carbon-carbon bonds for synthetic chemists. The chiral homoallylic and homopropargylic alcohols obtained from these reactions serve as versatile intermediates for the synthesis of natural and pharmaceutical products. Over the past three decades and continuing on, various synthetic groups around the globe have directed their research towards the efficient synthesis of these chiral moieties. In spite extensive research, asymmetric allylation and propargylation reactions remain an enduring challenge in organic chemistry. Chapter 1 of this thesis describes the first phosphoric acid catalyzed asymmetric allylboration of aldehydes. We found that the BINOL-derived phosphoric acids can efficiently catalyze the allylation reaction under specific conditions. Homoallylic alcohols were obtained in high yields and enantioselectivities from a wide variety of substrates. The optimized conditions were also found to be effective towards crotylboration of aldehydes. Chapter 2 describes the extension of the Br[o/]nsted acid catalyzed allylboration methodology to the propargylation of aldehydes. Homopropargylic alcohols were obtained with high selectivities with TRIP-PA as the catalyst. Synthesis of various important synthetic scaffolds from these chiral alcohols is also presented. The mechanistic insights studied by research groups of Kendall Houk and Jonathan Goodman have been outlined in chapter 3. These studies show that the major isomer is formed via a transition state involving the hydrogen bonding interaction between the hydroxyl group of the catalyst and the pseudoaxial oxygen of the boronate, with a stabilizing interaction of the phosphoryl oxygen to the formyl hydrogen. These insights helped us in developing new and highly efficient boronates that are described in the next chapter.

Alkylidene Meldrum’s acids are very reactive acceptors in conjugate additions, and are known to be significantly more electrophilic than other α,β-unsaturated carbonyl electrophiles. They also offer advantages in terms of ease of preparation, purification and storage. Despite this, they are relatively underused in organic synthesis, and have been treated as something of a curiousity in the literature. The goal of my research was to demonstrate the utility of these molecules in new reactions that are not readily available to other electrophiles. To facilitate this work, new conditions for the Knoevenagel condensation of aldehydes with Meldrum’s acid were developed. This allowed access to a broader range of monosubstituted alkylidenes than was previously possible from any single method. In a reaction that exploits the acylating ability of Meldrum’s acid, a domino addition of phenols to alkylidene Meldrum’s acids was developed. Here, Yb(OTf)3 catalyzed the addition of a phenol to the alkylidene as well as acylation through activation of the electrophile. The unique properties of these acceptors permitted synthesis of 3,4-dihydrocoumarins and coumarins through C-alkylation/O-acylation, and also 4-chromanones and chromones through O-alkylation/C-acylation. The predictable and general reversal of chemoselectivity is dependent on the number of substituents on the alkylidene. The same properties that make alkylidene Meldrum’s acids strong electrophiles also make them excellent dienophiles. A one-pot Diels-Alder/Friedel-Crafts process was used as an entry into the 6-5-6-tricyclic skeleton of a family of natural products that have been of interest in our group. The modular nature of the reaction allowed structural variation at nearly every position around both 6-membered rings. An attempted extension of this work into the synthesis of ergot alkaloids provided insight into the factors affecting Friedel-Crafts acylation of 4-substituted indoles. These results provided a highly regioselective entry into 4,5-fused indole ring systems. The electrophilicity of alkylidene Meldrum’s acids was combined with Lewis acid activation for development of a mild conjugate allylation reaction. The use of allyltriphenyltin as nucleophile for addition to monosubstituted alkylidenes avoided many of the practical disadvantages of working with trialkylstannanes. By employing such a relatively weak allylating agent, functional group compatibility was maximized to include groups susceptible to nucleophilic allylation. Additions to chiral, non-racemic alkylidenes were highly diastereoselective. It was also shown that functionalized all-carbon quaternary stereocentres can be formed by this process.

Alkylidene Meldrum’s acids are very reactive acceptors in conjugate additions, and are known to be significantly more electrophilic than other α,β-unsaturated carbonyl electrophiles. They also offer advantages in terms of ease of preparation, purification and storage. Despite this, they are relatively underused in organic synthesis, and have been treated as something of a curiousity in the literature. The goal of my research was to demonstrate the utility of these molecules in new reactions that are not readily available to other electrophiles. To facilitate this work, new conditions for the Knoevenagel condensation of aldehydes with Meldrum’s acid were developed. This allowed access to a broader range of monosubstituted alkylidenes than was previously possible from any single method. In a reaction that exploits the acylating ability of Meldrum’s acid, a domino addition of phenols to alkylidene Meldrum’s acids was developed. Here, Yb(OTf)3 catalyzed the addition of a phenol to the alkylidene as well as acylation through activation of the electrophile. The unique properties of these acceptors permitted synthesis of 3,4-dihydrocoumarins and coumarins through C-alkylation/O-acylation, and also 4-chromanones and chromones through O-alkylation/C-acylation. The predictable and general reversal of chemoselectivity is dependent on the number of substituents on the alkylidene. The same properties that make alkylidene Meldrum’s acids strong electrophiles also make them excellent dienophiles. A one-pot Diels-Alder/Friedel-Crafts process was used as an entry into the 6-5-6-tricyclic skeleton of a family of natural products that have been of interest in our group. The modular nature of the reaction allowed structural variation at nearly every position around both 6-membered rings. An attempted extension of this work into the synthesis of ergot alkaloids provided insight into the factors affecting Friedel-Crafts acylation of 4-substituted indoles. These results provided a highly regioselective entry into 4,5-fused indole ring systems. The electrophilicity of alkylidene Meldrum’s acids was combined with Lewis acid activation for development of a mild conjugate allylation reaction. The use of allyltriphenyltin as nucleophile for addition to monosubstituted alkylidenes avoided many of the practical disadvantages of working with trialkylstannanes. By employing such a relatively weak allylating agent, functional group compatibility was maximized to include groups susceptible to nucleophilic allylation. Additions to chiral, non-racemic alkylidenes were highly diastereoselective. It was also shown that functionalized all-carbon quaternary stereocentres can be formed by this process.

Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, selective silylallylation and CF₃-allylation were developed. In both cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Column chromatography was then tested as a new protocol to purify the iridium precatalyst; this single component precatalyst was proved to be more efficient to promote carbonyl crotylation reactions, both diastereo- and enantioselectivity were increased. Then, double asymmetric crotylation of 1,3-diols to deliver (pseudo-)C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of two known polypropionate natural product fragments of C19-C25 of scytophycin C, C19-C27 of rifamycin S and the total synthesis of 6-deoxyerythronolide B. / text

By simply hydrogenating enones in the presence of aldehydes at ambient temperature and pressure, aldol adducts are generated under neutral conditions in the absence of any stoichiometric byproducts. Using cationic rhodium complexes modified by tri(2-furyl)phosphine, highly syn-diastereoselective reductive aldol additions of vinyl ketones are achieved. Finally, using novel monodentate TADDOL-like phosphonite ligands, the first highly diastereo- and enantioselective reductive aldol couplings of vinyl ketones were devised. These studies, along with other works from our laboratory, demonstrate that organometallics arising transiently in the course of catalytic hydrogenation offer byproduct-free alternatives to preformed organometallic reagents employed in classical carbonyl addition processes. Existing methods for enantioselective carbonyl allylation, crotylation and tert-prenylation require stoichiometric generation of pre-metallated nucleophiles, and often employ stoichiometric chiral modifiers. Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium C,O-benzoate catalyst, enantioselective carbonyl allylations, crotylations and tert-prenylations are achieved in the absence of stoichiometric metallic reagents or stoichiometric chiral modifiers. Moreover, under transfer hydrogenation conditions, primary alcohols function dually as hydrogen donors and aldehyde precursors, enabling enantioselective carbonyl addition directly from the alcohol oxidation level. / text