<p>Allylic amines are important and fundamental building blocks due to their wide-spread occurrence in many natural products and the ability to further functionalize them by transformations on the double bond to generate a diverse range of compounds. Transition-metal catalyzed allylic substitution represents an attractive and efficient approach towards the synthesis of these allylic amines. However, limitations associated with the traditional methods developed for such allylic amination in terms of regiospecificity, atom economy and generality in these transformations, combined with the importance of allylic amination, prompted us to develop novel atom efficient and regiospecific methods for their synthesis.</p><p>A 1:1 mixture of AuCl[P(<italic>t</italic>-Bu)₂<italic>o</italic>-biphenyl] (5 mol %) and AgSbF₆ (5 mol %) catalyzed the intermolecular amination of underivatized allylic alcohols with 1-methyl-2-imidazolidinone and related nucleophiles. The first examples of intermolecular allylic amination was developed that in the case of gamma-unsubstituted and gamma-methyl-substituted allylic alcohols, occurred with high gamma-regioselectivity and <italic>syn</italic>-stereoselectivity.</p><p>A 1:1 mixture of AuCl[P(<italic>t</italic>-Bu)₂<italic>o</italic>-biphenyl] (5 mol %) and AgSbF₆ (5 mol %) also served as a very efficient catalytic system for the intramolecular amination of allylic alcohols with alkylamines to form substituted pyrrolidine and piperidine derivatives. The protocol was effective for a range of secondary as well as primary alkylamines as nucleophiles with different substitutions on the alkyl chain tethering the nucleophile to the allylic alcohol. The method was also extended towards the total synthesis of the naturally occurring alkaloid (S)-(+)-coniine in two steps from the starting (R,Z)-8-(N-benzylamino)-3-octen-2-ol. In addition, gold(I)-catalyzed cyclization of (R,Z)-8-(N-benzylamino)-3-octen-2-ol (96% ee) led to isolation of (R,E)-1-benzyl-2-(1-propenyl)piperidine in 99% yield and 96% ee that established the net syn-addition of the nucleophile with respect to the departing hydroxyl group.</p><p> A bis(gold) phosphine complex (S)-Au₂Cl₂(DTBM-MeOBIPHEP) (2.5 mol %) and AgClO₄ (5 mol %) catalyzed the intramolecular enantioselective dehydrative amination of allylic alcohols with carbamates to form the corresponding substituted pyrrolidines, piperidines, morpholines and piperazines in excellent yields and with up to 95% ee. This general and effective protocol tolerated a range of carbamates as well as sulfonamides as nucleophiles. Cyclization of chiral amino allylic alcohols that possessed a stereogenic homoallylic or hydroxy-bound carbon atom occurred with an overriding catalyst control of asymmetric induction. In addition, stereochemical analysis of the cyclization of a chiral non-racemic secondary allylic alcohol established the net syn-displacement of the hydroxy group by the carbamate nucleophile.</p><p>Alongside allylic amination, a cationic gold(I)-N-heteocyclic carbene complex catalyzed the intermolecular etherification (alkoxylation) of allylic alcohols in a regiospecific and syn-stereoselective fashion. The transformation was highly efficient to utilize unactivated primary and secondary alcohols as nucleophiles with different allylic alcohols to undergo regiospecific etherification. Employment of a chiral nonracemic secondary allylic alcohol, trans-5-(benzyloxy)pent-3-en-2-ol (98% ee) showed a high level of chirality transfer on reaction with n-butanol to the corresponding allylic ether, (2-butoxypent-3-en-1-yloxy)methylbenzene (97% ee) and established the net syn-addition of the alcohol nucleophile with respect to the departing hydroxyl group of the allylic alcohol.</p> / Dissertation

<p>Numerous methodologies for efficient formation of carbon-nitrogen bonds have been developed over the decades due to the widespread importance of nitrogen containing compounds in pharmaceuticals and bulk commercial chemicals. Among many methods, hydroamination, especially, has attracted enormous attention because of its atom-economical characteristic to synthesize amine moieties. As a result, numerous publications have been reported relating the hydroamination reaction using various metal catalysts. However, the hydroamination of unactivated alkenes still remains a challenge task because of the low reactivity of the CC double bond. Recent development of superior gold(I) catalysis in many organic transformations stimulated us to develop efficient gold(I)-catalyzed methods for enantioselective intra- and intermolecular hydroamination of unactivated alkenes. </p><p>A gold(I)-catalyzed system for enantioselective intramolecular hydroamination of unactivated alkenes has been developed. For the effective gold(I)-catalyzed method, various gold(I)-catalysts have been synthesized and tested. Among the catalysts, bis(gold) complexes containing an axially chiral bis(phosphine) ligand catalyze the enantioselective intramolecular hydroamination of unactivated alkenes with carboxamide derivatives, most effectively. The method was effective for both carbamates and ureas to form pyrrolidine derivatives with up to 85 % ee.</p><p>The first enantioselective intermolecular hydroamination of unactivated alkenes was realized by a gold(I)-catalyzed method. The gold(I) catalyst system adds cyclic ureas to unactivated 1-alkenes to produce corresponding enantiomerically enriched hydroamination product in good yield with enantioselectivity up to 78 % ee. </p><p>Polymer-embedded ligands have been synthesized to demonstrate proofs of concepts for fluxional mechanocatalysis. We applied a certain shear stress using a rheometer in the course of palladium-catalyzed asymmetric allylic alkylation to examine catalytic reactivity change under the mechanical force.</p> / Dissertation

This dissertation focuses on the computational investigation of gold(I) acyclic diaminocarbene (ADC) complexes and their application in homogeneous gold(I) catalysis. Chapter 2 is an in-depth computational investigation of the σ- and π-bonding interactions that make up the gold-carbene bond. Due to the inherent conformation flexibility of ADC ligands, distortions of the carbene plane can arise that disrupt orbital overlap between the lone pairs on the adjacent nitrogen atoms and the empty p-orbital of the carbene. This study investigated the affect these distortions have on the strength of the σ- and π-bonding interactions. This investigation demonstrated that while these distortions can affect the σ- and π-bonding interactions, the ADC ligand have to become highly distorted before any significant change in energy of either the σ- or π-bonding interactions occurs. Chapter 3 is a collaborative investigation between experimental and computational methods, DFT calculations were employed to support the experimental catalytic results and determine the role that steric effects have in controlling the regioselectivity of a long-standing electronically controlled gold(I)-catalyzed tandem 1,6-enyne cyclization/hydroarylation reaction with indole. This study demonstrated that by sterically hindering nucleophilic attack of indole at the favored position, nucleophilic attack would occur at a secondary position leading to the selective formation of the electronically unfavored product. Chapter 4 is a collaborative investigation between experimental and computational methods. DFT calculations were employed to investigate and rationalize the importance of secondary non-covalent interactions and their influence on the enantioselectivity of a gold(I)-catalyzed intramolecular hydroamination of allene reaction. Through computational investigation of the enantiodetermining step, and the non-covalent interactions present between 2′-aryl substituent and the rest of the catalyst, it was determined that the presence of CF3 group on the 3,5-position of the 2′-aryl ring is crucial to maintaining a more rigid chiral pocket leading to higher enantiomeric excesses in this dynamic system. This increased rigidity is believed to be attributable to the several weak non-covalent interactions that arise between the allene substrate or diisopropyl N-substituent and the fluorine atoms of the CF3 groups.

Gold catalysis has become an important tool to achieve highly chemoselective p-acid activation. Exceptional reactivity and selectivity are often encountered under mild reaction conditions. These properties have made gold(I) complexes suitable catalysts for tremendous applications in the total synthesis of natural products. The first chapter will highlight a number of total syntheses using gold catalysis as a key step. The second chapter will cover our application of the gold(I)-catalyzed 6-endo-dig carbocyclization for the synthesis of bridgehead-substituted scaffolds and its use toward the synthesis of PPAP natural products. This research has opened our eyes to the utility of biphenylphosphine ligands, particularly JohnPhos, in gold(I)-catalysis. The reactivity and selectivity exhibited by gold(I) complexes is modulated by the nature of the ancillary ligand. Recent research rationalizes the impact of these ligands on the divergent reactivity observed between cationic and carbenoid intermediates. Our desire to favor the 6-endo-dig pathway has led us toward the discovery of another example of the diagonal reactivity that NHC carbene and biphenylphosphine ligands can bring to gold(I)-catalysis. Chapter three will explain the development of a selective gold-catalyzed synthesis of fused carbocycles . Our selective divergent synthesis of fused carbocycles, combined with the Diels–Alder reaction, has brought new synthetic opportunities. Chapter four will describe our approach toward the synthesis of various polycyclic diterpene-related frameworks. Starting with a unique linear precursor, we have developed a new “one-pot” process for the synthesis of three different polycyclic compounds related to the terpenoid family. The facile modulation of the linear precursor and the use of different dienophiles during the Diels–Alder reaction could enable the synthesis of diverse polycyclic analogues based on three principal frameworks. The gold(I)-catalyzed synthesis of fused carbocycles reached some limitations during our study. Regioselective control was found to be substantially more challenging, with terminal alkynes or alkynes bearing a sterically and electronically neutral methyl substituent. In chapter five, we will discuss how the complementarity of silver(I) catalysis to gold(I) catalysis enabled the selective divergent synthesis of three different fused carbocycles from a unique precursor. Moreover, copper(I) catalysis has given access to the 6-endo-dig pathway on terminal alkynes without the formation of a vinylidene intermediate.

Gold catalysis has become an important tool to achieve highly chemoselective p-acid activation. Exceptional reactivity and selectivity are often encountered under mild reaction conditions. These properties have made gold(I) complexes suitable catalysts for tremendous applications in the total synthesis of natural products. The first chapter will highlight a number of total syntheses using gold catalysis as a key step. The second chapter will cover our application of the gold(I)-catalyzed 6-endo-dig carbocyclization for the synthesis of bridgehead-substituted scaffolds and its use toward the synthesis of PPAP natural products. This research has opened our eyes to the utility of biphenylphosphine ligands, particularly JohnPhos, in gold(I)-catalysis. The reactivity and selectivity exhibited by gold(I) complexes is modulated by the nature of the ancillary ligand. Recent research rationalizes the impact of these ligands on the divergent reactivity observed between cationic and carbenoid intermediates. Our desire to favor the 6-endo-dig pathway has led us toward the discovery of another example of the diagonal reactivity that NHC carbene and biphenylphosphine ligands can bring to gold(I)-catalysis. Chapter three will explain the development of a selective gold-catalyzed synthesis of fused carbocycles . Our selective divergent synthesis of fused carbocycles, combined with the Diels–Alder reaction, has brought new synthetic opportunities. Chapter four will describe our approach toward the synthesis of various polycyclic diterpene-related frameworks. Starting with a unique linear precursor, we have developed a new “one-pot” process for the synthesis of three different polycyclic compounds related to the terpenoid family. The facile modulation of the linear precursor and the use of different dienophiles during the Diels–Alder reaction could enable the synthesis of diverse polycyclic analogues based on three principal frameworks. The gold(I)-catalyzed synthesis of fused carbocycles reached some limitations during our study. Regioselective control was found to be substantially more challenging, with terminal alkynes or alkynes bearing a sterically and electronically neutral methyl substituent. In chapter five, we will discuss how the complementarity of silver(I) catalysis to gold(I) catalysis enabled the selective divergent synthesis of three different fused carbocycles from a unique precursor. Moreover, copper(I) catalysis has given access to the 6-endo-dig pathway on terminal alkynes without the formation of a vinylidene intermediate.

De nouveaux processus de cyclisation d’allènes fonctionnalisés catalysées par des triflates métalliques sont présentés. Deux stratégies ont été développées. Dans un premier temps, une réaction de type carbonyl-ène intramoléculaire à partir de cétones γ-alléniques est développée. Cette réaction se déroule dans des conditions très douces avec une charge catalytique en triflate de bismuth(III) de seulement 1 mol%. Cette stratégie a ensuite été étendue à d’autres dérivés cétones γ-alléniques. Les alcools diéniques résultants ont pu être engagés avec succès dans une réaction de type Diels-Alder menant à la formation de structures polycycliques fonctionnalisées avec de bons rendements et une excellente régio- et diastéréosélectivité. La cyclisation d’éthers d’énol catalysée par les triflates métalliques a été par la suite étudiée. Cette stratégie permet d’obtenir des dérivés cyclopentènes avec de bons rendements en utilisant seulement 0,1 mol% de triflate de bismuth(III). Des dérivés dihydrofuranes peuvent être également formés par cette stratégie. Ces produits résultent de l’attaque nucléophile du carbone central de l’allène sur l’éther d’énol activé. Cette réactivité a pu être inversée en utilisant un complexe d’or(I) comme catalyseur en présence d’un nucléophile externe, donnant ainsi naissance à des produits différents. Dans une dernière partie, des applications dans le domaine de la chimie des arômes et des parfums ont été développées. Des dérivés acétates et alcools alléniques ont été synthétisés et exposés à des tests olfactifs, révélant des tonalités olfactives intéressantes. Des notes fruitées et florales dominantes et des nuances vertes et boisées ont été détectées. / Novel processes of metal triflate-catalyzed cyclizations of functionalized allenes are presented. Two strategies have been developed. In a first part, the intramolecular carbonyl-ene reaction with γ-allenic ketones is described. This reaction proceeds under very mild conditions using only 1 mol% of bismuth(III) triflate. The scope of this reaction was extended to several γ-allenic ketone derivatives, featuring various substitution patterns. The resulting dienols were successfully engaged in a Diels-Alder reaction allowing the formation of polycyclic functionalized frameworks in good yields with excellent regio- and diastereoselectivities. In a second part, the metal triflate-catalyzed cyclization of allenic-enol ethers is described. This reaction gives access to cyclopentene derivatives in good yields using only 0.1 mol% of bismuth(III) triflate. Dihydrofuran derivatives could also be formed using this strategy. This cycloisomerisation reaction proceeds through an initial enol ether activation, followed by the nucleophilic attack of the allene moiety. This reactivity could be inverted using a gold(I) catalyst, in the presence of an exogenous nucleophile, allowing the formation of different products. Within our interest in flavor and fragrance chemistry, allenic acetates and alcohols have been synthesized and subjected to olfactive evaluation, revealing dominant fruity and floral notes. Green and woody undertones have been detected as well.