Asymmetric conjugate addition of bis(pinacolato)diboron followed by aldol cyclisation of enone diones under the action of a chiral copper catalyst has been developed. This enantioselective process, using a chiral bisphosphine as ligand, allows the formation of bicyclic alcohols with four contiguous stereocentres in high diastero- and enantioselectivity. This catalytic system has been applied to the parallel kinetic resolution of a racemic β- ketoamide. Further functionalization of the bicyclic alcohols synthesised was also possible. A domino addition of arylboronic acids and cyclisation of alkynones via an undescribed iridium 1-4-migration process has been developed. A range of tricyclic compounds using a variety of arylboronic acids have been synthesised in good yields and high diasteroselectivity. The use of chiral bisphosphine ligand together with an iridium salt allows the formation of enantioenriched compounds in moderate yield.

We have described two important classes of palladium-catalyzed reactions for the synthesis of heterocycles and carbocycles: tandem Pd-catalyzed reactions of gem-dibromoolefins and domino Pd-catalyzed reactions via an ortho C−H functionalization. Chapter 1 describes the tandem Pd-catalyzed reaction of gem-dibromoolefins via an intramolecular direct arylation and an intermolecular Suzuki-Miyaura cross-coupling. A number of aromatic carbocycles were synthesized by this method. Chapter 2 describes the tandem Pd-catalyzed reactions of β,β-dibromoenamides via an intramolecular C−O bond formation and an intermolecular Suzuki-Miyaura cross-coupling. Depending on the substituent on the nitrogen of β,β-dibromoenamides, either aromatic heterocycles or acyclic compounds can be synthesized. Chapter 3 and 4 describe the domino Pd-catalyzed reactions via an ortho C−H functionalization of aryl iodides. 2-Pyrrole substituted phenyl iodides were coupled with alkyl bromides in the presence of norbornene to provide aromatic tetracyclic compounds through three C−C bond formations (Chapter 3). However, the reaction between 2-methyl substituted phenyl iodides and the alkyl bromides in the presence of norbornene provided tetrasubstituted helical alkenes with the norbornene incorporated in the final product through four C−C bond formations (chapter 4). In Chapter 5, detailed mechanistic studies including kinetic and NMR studies were described for the regioselective C−H functionalization of 2-pyrrole substituted phenyl iodides. The studies provided advanced and important understanding of the mechanism, and a rationale for the high regioselectivity.

We have described two important classes of palladium-catalyzed reactions for the synthesis of heterocycles and carbocycles: tandem Pd-catalyzed reactions of gem-dibromoolefins and domino Pd-catalyzed reactions via an ortho C−H functionalization. Chapter 1 describes the tandem Pd-catalyzed reaction of gem-dibromoolefins via an intramolecular direct arylation and an intermolecular Suzuki-Miyaura cross-coupling. A number of aromatic carbocycles were synthesized by this method. Chapter 2 describes the tandem Pd-catalyzed reactions of β,β-dibromoenamides via an intramolecular C−O bond formation and an intermolecular Suzuki-Miyaura cross-coupling. Depending on the substituent on the nitrogen of β,β-dibromoenamides, either aromatic heterocycles or acyclic compounds can be synthesized. Chapter 3 and 4 describe the domino Pd-catalyzed reactions via an ortho C−H functionalization of aryl iodides. 2-Pyrrole substituted phenyl iodides were coupled with alkyl bromides in the presence of norbornene to provide aromatic tetracyclic compounds through three C−C bond formations (Chapter 3). However, the reaction between 2-methyl substituted phenyl iodides and the alkyl bromides in the presence of norbornene provided tetrasubstituted helical alkenes with the norbornene incorporated in the final product through four C−C bond formations (chapter 4). In Chapter 5, detailed mechanistic studies including kinetic and NMR studies were described for the regioselective C−H functionalization of 2-pyrrole substituted phenyl iodides. The studies provided advanced and important understanding of the mechanism, and a rationale for the high regioselectivity.

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.

In this thesis the synthesis of vicinal stereocenters is investigated in two distinct contexts, namely the construction of 3,3-disubstituted oxindoles and the synthesis of b-hydroxy-a-amino acids. Both scaffolds are prevalent in a range of natural products and biologically relevant compounds and, therefore, methods for their synthesis are of great import. First, the construction of 3,3-disubstituted oxindoles using palladium-catalyzed domino reactions is described.  This covers two stereospecific methods for the construction of the desired oxindoles based on domino carbopalladation sequences.  The termination events for these domino reactions are carbonylation or cross-coupling.  In the carbopalladation-carbonylation reaction, we studied the possibilty of suppressing b-hydride elimination for substrates possessing pendant b-hydrogens.  In the carbopalladation-cross-coupling sequence, we examined the role of the boron source and substrate scaffold in the outcome of the reaction.  In both of these methods, an intricate balance of rates needs to be attained in order to achieve the desired domino sequences.  Thus, these investigations offer insight into the rates of the competing reactions, and the factors that influence these processes. Secondly, the stereoselective synthesis of b-hydroxy-a-amino acids is explored.  This has lead to two separate methods for the construction of this scaffold.  We first examined a 1,3-dipolar cycloaddition of azomethine ylides to aldehydes for the construction of syn-b-hydroxy-a-amino esters.  It was found that one set of azomethine ylides reacted through a 1,3-dipolar cycloaddition, while the other set reacted via a direct aldol reaction.  Finally, we studied an asymmetric transfer hydrogenation reaction to provide anti-b-hydroxy-a-amido esters from the corresponding a-amido-b-ketoesters.  Two protocols were developed for the reduction of these substrates, one using triethylammonium formate and the other using sodium formate in an emulsion.  The latter method gives high yields, diastereoselectivities and enantioselectivities for a broad range of substrates. / QC 20120605

The Lautens group has a long-standing interest in developing novel approaches to heterocycle synthesis. One such approach is a Pd-catalyzed, norbornene-mediated domino reaction which can form up to three carbon-carbon bonds in one synthetic sequence. The key additive is norbornene which acts similar to a catalyst by assembling the scaffold to enable the formation of a carbon-carbon bond, though is not incorporated into the final compound. The reaction involves C-H bond functionalization as a key step and a Pd(IV) complex as a key intermediate. The goal of the current thesis was to introduce reactive heteroatoms to this domino reaction for the first time, with particular focus on the introduction of nitrogen. Methodologies were developed to present novel syntheses of heterocycles with high pharmaceutical interest. Our initial study focused on the selective functionalization of thiophenes to give multi-substituted sulfur compounds. To synthesize pharmaceutically important nitrogen heterocycles, we demonstrated for the first time that an amination reaction was compatible with the domino reaction. This development led to novel approaches to synthesize substituted indolines, indoles, tetrahydroquinolines, benzomorpholines, phenoxazines, dihydrodibenzoxazepines, tetrahydroisoquinolines, tetrahydroisoquinolinones and tetrahydrobenzazepines. In contrast to the use of norbornene in a catalytic manner, we demonstrated that heterocycles could also be synthesized by the incorporation of strained alkenes. We developed a conceptually novel approach to generate nitrogen heterocycles by using norbornadiene as an acetylene synthon. A palladium-catalyzed annulation of substituted haloanilines with norbornadiene led to functionalized indolines. These indolines could be rapidly converted to benzenoid-substituted indoles and tricyclic indolines, which form the core of many biologically active compounds. Extension to the use of substituted halobenzamides led to functionalized isoquinolinones. Finally, we embarked on a study to perform selective palladium-catalyzed C-H functionalization reactions with N-iodoarylpyrroles and strained alkenes. We will present the reaction conditions necessary to favour aryl C-H functionalization over pyrrole C-H functionalization.

The development of a novel palladium-catalyzed domino reaction with indole-based gem-dibromoolefin substrates is described. The reaction allowed access to a new class of polycyclic nitrogen heterocycles: N-fused benzo[c]carbazoles. A key feature of this domino reaction was the participation of both bromides in C–H functionalization processes, a hitherto unprecedented reactivity. Various substituents and substitution patterns were tolerated in this reaction, allowing for a highly modular approach to these challenging synthetic targets. Mechanistic studies were performed to gain further insight into the reactivity of these systems and elucidate the sequence of reaction steps. The results indicate that isomerization of reaction intermediates likely played a key role in promoting a successful reaction.

The development of a novel palladium-catalyzed domino reaction with indole-based gem-dibromoolefin substrates is described. The reaction allowed access to a new class of polycyclic nitrogen heterocycles: N-fused benzo[c]carbazoles. A key feature of this domino reaction was the participation of both bromides in C–H functionalization processes, a hitherto unprecedented reactivity. Various substituents and substitution patterns were tolerated in this reaction, allowing for a highly modular approach to these challenging synthetic targets. Mechanistic studies were performed to gain further insight into the reactivity of these systems and elucidate the sequence of reaction steps. The results indicate that isomerization of reaction intermediates likely played a key role in promoting a successful reaction.

The Lautens group has a long-standing interest in developing novel approaches to heterocycle synthesis. One such approach is a Pd-catalyzed, norbornene-mediated domino reaction which can form up to three carbon-carbon bonds in one synthetic sequence. The key additive is norbornene which acts similar to a catalyst by assembling the scaffold to enable the formation of a carbon-carbon bond, though is not incorporated into the final compound. The reaction involves C-H bond functionalization as a key step and a Pd(IV) complex as a key intermediate. The goal of the current thesis was to introduce reactive heteroatoms to this domino reaction for the first time, with particular focus on the introduction of nitrogen. Methodologies were developed to present novel syntheses of heterocycles with high pharmaceutical interest. Our initial study focused on the selective functionalization of thiophenes to give multi-substituted sulfur compounds. To synthesize pharmaceutically important nitrogen heterocycles, we demonstrated for the first time that an amination reaction was compatible with the domino reaction. This development led to novel approaches to synthesize substituted indolines, indoles, tetrahydroquinolines, benzomorpholines, phenoxazines, dihydrodibenzoxazepines, tetrahydroisoquinolines, tetrahydroisoquinolinones and tetrahydrobenzazepines. In contrast to the use of norbornene in a catalytic manner, we demonstrated that heterocycles could also be synthesized by the incorporation of strained alkenes. We developed a conceptually novel approach to generate nitrogen heterocycles by using norbornadiene as an acetylene synthon. A palladium-catalyzed annulation of substituted haloanilines with norbornadiene led to functionalized indolines. These indolines could be rapidly converted to benzenoid-substituted indoles and tricyclic indolines, which form the core of many biologically active compounds. Extension to the use of substituted halobenzamides led to functionalized isoquinolinones. Finally, we embarked on a study to perform selective palladium-catalyzed C-H functionalization reactions with N-iodoarylpyrroles and strained alkenes. We will present the reaction conditions necessary to favour aryl C-H functionalization over pyrrole C-H functionalization.

No description available.