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.

The development of novel asymmetric reaction methodologies has been invaluable in both the academic and industrial world. In just 15 years, organocatalysis has provided a new means of developing asymmetric reaction methodologies using catalysts that are environmentally benign, relatively inexpensive, bench stable, and non-toxic. One development in organocatalysis that is important to our group in particular is chiral phosphoric acid-catalysis. BINOL-derived and VAPOL-derived phosphoric acids have proven to be excellent catalysts for a number of reactions. The two projects I will discuss my efforts on are acetalization and iso-Pictet-Spengler reactions. These were projects that I performed during my first two years as a graduate student. The acetalization was particularly fascinating as only one literature report existed for the catalytic asymmetric variant of a reaction that makes such important compounds--O,O-acetals. The acetalization reaction proved to be a formidable opponent, and to this date no research report has been published documenting the intra-, or intermolecular catalytic asymmetric acetalization of vinyl ethers or the intermolecular catalytic asymmetric transacetalization. The iso-Pictet-Spengler reaction is one that is interesting because exhaustive research has been conducted into the development of catalytic asymmetric Pictet-Spengler reactions, but at the time of my research, not a single catalytic asymmetric method existed to synthesize tetrahydro-γ-carbolines, the product of the iso-Pictet-Spengler reaction. Structurally, the tetrahydro-γ-carboline is isomeric to the tetrahydro-β-carboline, the product of the Pictet-Spengler reaction. They differ only in the position of nitrogen in the annulated product. This reaction seemed attractive to investigate, since independent elegant reports by Professors Benjamin List, Henk Hiemstra, and Darren Dixon documented the excellent control over enantioselectivity that chiral phosphoric acid have in the Pictet-Spengler reaction. Concurrent with the beginning stages of this project, Professor Eric Jacobsen reported the enantioselective thiourea-catalyzed iso-Pictet-Spengler reaction. The results were very good but not as great as the Pictet-Spengler work he pioneered. Around the time this report came out I commenced my reaction studies, and this thesis is the sum of just two projects I worked on. There were many more including halolactonization, VAPOL synthesis, chiral phosphoric acid synthesis, catalytic asymmetric hydroamination, and others.

Asymmetric synthesis and catalysis is one of the leading research areas in chemistry society, for its versatility and efficiency in obtaining chiral molecules that found the vast majority in natural active compounds and synthetic drugs. Developing asymmetric catalytic methodology is at the frontier in both industrial and academic research laboratories. Enantioselective organocatalysis has emerged as a powerful synthetic tool that is complementary to metal-catalyzed transformations. The development of chiral phosphoric acid and metal phosphate as catalysts has been a breakthrough in recent years. Chiral phosphoric acids have been shown to be powerful catalysts in many organic transformations. Moreover, chiral metal phosphates, which formed by simply replacing the proton in phosphoric acid with metals, have introduced new catalytic activations and broaden the scope of phosphoric acids. This thesis details new highly enantioselective chiral phosphoric acid-catalyzed Pinacol rearrangement and robust alkaline phosphates catalytic system, which utilizes novel carbonyl activation. The Pinacol rearrangement has long been known to be difficult to control in terms of regioselectivity and stereoselectivity. The initial studies found that indolyl-diol compounds can be treated with chiral phosphoric acids to afford the Pinacol rearrangement with high regio- and enantioselectivity. Over 16 chiral phosphoric acids were screened, and it was found an H8-BINOL-phosphoric acid variant with 1-naphthyl groups at 3 and 3' position was the excellent catalyst. This asymmetric transformation is tolerant toward variety of substituents both on the indole ring and migrating groups. During the study, it was found that different ways to generate the catalyst had critical effect on this catalytic transformation. Only those phosphoric acids washed with HCl after column chromatography afforded the rearrangement products with high enantioselectivity. And those without treating with HCl were found contaminated by alkaline metals. These "contamination" catalysts were also found active with carbonyl activations. A highly enantioselective catalytic hetero-Diels-Alder reaction of alpha-keto esters has been developed with chiral alkaline metal phosphates. A calcium 1-naphthyl-BINOL phosphate was found to be the optimum catalyst. A large range of alpha-keto esters as well as isatins can be applied in this alkaline phosphates catalytic system with high efficiency and selectivity. The structure of the catalyst is detailed for the first time by X-ray crystal structure analysis. A proposed Transition state model is provided based on the catalyst crystal structure and Raman spectroscopy analysis. This methodology was further developed with an asymmetric Mukaiyama-Michael addition of beta,gamma-unsaturated alpha-keto ester. The best catalyst was found to be a magnesium chiral phosphate. And the transformation was found capable of tolerating a wide variety of beta,gamma-unsaturated alpha-keto esters.

Ce travail porte sur l’étude de la réaction de Povarov, une réaction de type aza-Diels-Alder à demande inverse d’électrons entre un diène de type 2-aza-diène (généralement une imine dérivée d’une aniline) et un diénophile tel qu’une oléfine riche en électrons, aboutissant ainsi à la formation de tétrahydroquinoléines. Nous sommes parvenus à réaliser cette réaction dans sa version multicomposants, c’est-à-dire en formant in situ l’imine à partir de l’aldéhyde et de l’aniline correspondants. De plus, cette réaction multicomposants a pu être effectuée de manière énantiosélective, en utilisant comme catalyseur des organocatalyseurs de type acides phosphoriques chiraux, et en choisissant judicieusement comme diénophile des ène-carbamates, qui possèdent une liaison N-H capable d’interagir avec l’acide phosphorique. Cette méthodologie a ainsi permis la synthèse de 4-amino-tétrahydroquinoléines avec une diastéréosélectivité totale, de bons rendements, et d’excellents excès énantiomériques. L’utilisation de diénophiles de type ène-thiourées a permis selon la même stratégie d’accéder à des composés hexahydropyrroloquinoléines avec des sélectivités similaires.Nous nous sommes également intéressés au mécanisme de cette réaction de Povarov, qui s’est révélé se dérouler en deux étapes distinctes, l’intermédiaire immonium pouvant être piégé, soit de manière intermoléculaire par l’éthanol, conduisant après réduction à des 1,3-diamines chirales, soit de manière intramoléculaire dans le cas particulier de l’utilisation du phénylacétaldéhyde, conduisant alors à des 1,3-diaminotétralines. / This work deals with the Povarov reaction, an inverse electron-demanding Diels-Alder reaction between 2-aza-dienes (generally an N-aryl-imine) and a dienophile such as an electron-rich olefin, leading to the formation of tetrahydroquinolines. We were able to perform this reaction in a multicomponent way, ie by the in situ formation of the imine from the corresponding aldehyde and aniline. Moreover, this multicomponent reaction was also énantiosélective, by using chiral phosphoric acids as catalysts, and by choosing enecarbamates as diénophiles, which could interact with the catalyst thanks to their N-H bond. This methodology allowed to synthesize 4-amino-tetrahydroquinolines in good yields with total diastereoselectivities and excellent enantioselectivities. The use of ene-thioureas as dienophiles also allowed to synthesize hexahydropyrroloquinolines with the same selectivities, following the same method.We also studied the mechanism of this Povarov reaction. We proved that it is a stepwise mechanism, by trapping the iminium intermediate, either via an intermolecular reaction with ethanol leading to chiral 1,3-diamines, or via an intramolecular reaction in the particular case of phenylacetaldehyde, then leading to 1,3-diaminotetralins.