Thesis advisor: Amir H. Hoveyda / Formation of C-C bonds is an invaluable tool for the construction of materials, pharmaceuticals, natural products, and the building blocks of life. Although great strides in this area have been made, there remain several limitations in regio-, site-, and enantioselective additions of carbon-based nucleophiles. Solving these challenges by expanding the scope, efficiency, and selectivity of alkyl, aryl, heteroaryl, vinyl, and alkynyl additions to carbon-based electrophiles is the topic of this dissertation. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

In this diploma Thesis I dealt with the synthesis of nitrogen compounds that contain quaternary carbon centres and their structure resembles natural substances, specifically alkaloids from the Amaryllidaceae family. Halocarbocyclization or Heck reaction was planned as a key step of the synthesis, which should lead to the formation of quaternary carbon centres. First, starting nitriles and esters with five- and six-membered rings were prepared. Subsequently, the method for the preparation of a stable bicyclic ketone with a five-membered ring from an ester was optimized. The next part of the Thesis is devoted to the synthesis of a substrate for the Heck reaction from the prepared ketone, which was then used for the preparation of the alkaloid skeleton with a quaternary carbon centre, unfortunately without success so far. In the last part of the work, a bicyclic ketone with a six-membered ring, from which it is possible to prepare a substrate for the Heck reaction in several steps already used for five-membered substances, was prepared from the nitrile by carbopalladation. Key words: synthesis, quaternary carbon centres, Heck reaction, halocarbocyclisation, Amaryllidaceae alkaloids

Chiral molecules play a central role in our daily life and in nature, for instance the different enantiomers or diastereomers of a chiral molecule may show completely different biological activity. For this reason, it is a vital goal for synthetic chemists to design selective and efficient methodologies that allow the synthesis of the desired enantiomer. In this context, it is highly important that the concept of green chemistry is considered while designing new approaches that eventually will provide more environmental and sustainable chemical synthesis.The aim of this thesis is to develop the concept of combining transition metal catalysis and aminocatalysis in one process (dual catalysis). This strategy would give access to powerful tools to promote reactions that were not successful with either transition metal catalyst or the organocatalyst alone. The protocols presented in this thesis based on organocatalytic transformations via enamine or iminium intermediates or both, in combination with transition metal catalysis, describes new enantioselective organocatalytic procedures that afford valuable compounds with high chemo- and enantioselectivity from inexpensive commercial available starting materials. In paper I, we present a successful example of dual catalysis: the combination of transition metal activation of an electrophile and aminocatalyst activation of a nucleophile via enamine intermediate. In paper II, the opposite scenario is presented, here the transition metal activates the nucleophile and the aminocatalyst activates the electrophile via an iminium intermediate. In paper III,we present a domino Michael/carbocyclisation reaction that is catalysed by a chiral amine (via iminium/enamine activation) in combination with a transition metal catalysts activation of an electrophile. In paper IV, the concept of dual catalysis was further extended and applied for the highly enantioselective synthesis of valuable structural scaffolds, namely poly-substituted spirocyclic oxindoles. Finally, in paper V the concept of dual catalysis was expanded, by investigating more challenging and environmentally benign processes, such as the successful combination of a heterogeneous palladium and amine catalysts for the highly enantioselective synthesis of functionalised cyclopentenes, containing an all carbonquaternary stereocenter, dihydrofurans and dihydropyrrolidines.

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Investigation of the catalytic formation, reactivity and synthetic scope of sp³-gem-organodimetallic palladio(II)/main group metal (main group metal = tributylstannyl, dialkylalumino) alkane species has been carried out. Insight was expanded regarding the inter- and intramolecular reactivity of vinylmetallic reagents in presence of transition metal catalysts. New Pd-catalysed methodologies for carbon-carbon bond formation were developed, such as cyclopropanation of strained olefins, as well as tandem vinylalane arylation/1,2-methyl transfer and 1,2-diarylation. On the one hand, geminal π-allylpalladio(II)/tributylstannylalkane intermediates are produced by oxidative addition of Pd(0) catalysts to α-tributylstannylpropenyl acetate derivatives. They adopt ambiphilic behaviour depending on the transition metal pre-catalyst, presence or absence of phosphine ligands, and reaction temperature. In presence of tetrakis(triphenylphosphine)palladium(0) with additional bidentate ligand, the carbenoid reactivity of these gem-organobismetallic species is exposed by reaction with dimethyl malonate. Deuterium-labeling studies demonstrated sequential functionalisation of the C-Sn and C-Pd bonds. Conversely, phosphine-free catalyst bis(dibenzylideneacetone)palladium(0) uncovers metal-carbene reactivity, and dimerisation and strained alkene cyclopropanation reactions are observed. The nature of the palladium catalyst controls the reactivity of the carbenoid species. Finally, bis(cyclooctadienerhodium(I) chloride) catalytically activates the alkenylstannane moiety, leaving the allylic acetate leaving group available for further transformations. On the other hand, gem-disubstituted trifluoromethanesulfonyloxy- and iodopalladio(II)/ dialkylaluminoneopentane species are generated by intramolecular migratory insertion of 2,2-disubstituted-1-butenyldialkylalanes with σ-arylpalladium(II) triflate and iodide intermediates. Using excess Lewis-basic 1,4-diazabicyclo[2.2.2]octane, electron-rich tris(para-methoxyphenyl)phosphine ligand and acetonitrile as solvent, tandem arylation/1,2-alkyl migration from aluminum to carbon affords 7-substituted-1-ethyl-1-methylindanes containing an all-carbon quaternary stereogenic centre in good yields. This reaction is tolerant of 6-aryl methyl ethers, thioethers and trimethylsilanes. Deuterium labeling established that protiodealumination of the key neopentyl(methyl)aluminum triflate intermediate is caused by the acetonitrile solvent. The organodimetallic species in that study were shown to be configurationally stable, hence the stereospecificity of the process that proceeds via carbopalladation, transmetalation and reductive elimination of an alkylpalladium(II) intermediate. When applied to 1-naphthyl triflate-tethered vinylalanes, the same reaction conditions mediate stereospecific 1,2-diarylation, leading to 2,3,3a,4-tetrahydro-1H-cyclopenta[def]phenanthrenes in excellent yields. The influence of DABCO, tether length and solvent polarity was studied. Selective tandem arylation/1,2-methyl migration could also be achieved in non-polar solvent in absence of Lewis base. While steric properties took precedence over electronic considerations when inducing product selection, preagostic C-H···Pd interactions were postulated to facilitate 1,3-metal migration in the production of 1H-cyclopenta[def]phenanthrene derivatives.

Investigation of the catalytic formation, reactivity and synthetic scope of sp³-gem-organodimetallic palladio(II)/main group metal (main group metal = tributylstannyl, dialkylalumino) alkane species has been carried out. Insight was expanded regarding the inter- and intramolecular reactivity of vinylmetallic reagents in presence of transition metal catalysts. New Pd-catalysed methodologies for carbon-carbon bond formation were developed, such as cyclopropanation of strained olefins, as well as tandem vinylalane arylation/1,2-methyl transfer and 1,2-diarylation. On the one hand, geminal π-allylpalladio(II)/tributylstannylalkane intermediates are produced by oxidative addition of Pd(0) catalysts to α-tributylstannylpropenyl acetate derivatives. They adopt ambiphilic behaviour depending on the transition metal pre-catalyst, presence or absence of phosphine ligands, and reaction temperature. In presence of tetrakis(triphenylphosphine)palladium(0) with additional bidentate ligand, the carbenoid reactivity of these gem-organobismetallic species is exposed by reaction with dimethyl malonate. Deuterium-labeling studies demonstrated sequential functionalisation of the C-Sn and C-Pd bonds. Conversely, phosphine-free catalyst bis(dibenzylideneacetone)palladium(0) uncovers metal-carbene reactivity, and dimerisation and strained alkene cyclopropanation reactions are observed. The nature of the palladium catalyst controls the reactivity of the carbenoid species. Finally, bis(cyclooctadienerhodium(I) chloride) catalytically activates the alkenylstannane moiety, leaving the allylic acetate leaving group available for further transformations. On the other hand, gem-disubstituted trifluoromethanesulfonyloxy- and iodopalladio(II)/ dialkylaluminoneopentane species are generated by intramolecular migratory insertion of 2,2-disubstituted-1-butenyldialkylalanes with σ-arylpalladium(II) triflate and iodide intermediates. Using excess Lewis-basic 1,4-diazabicyclo[2.2.2]octane, electron-rich tris(para-methoxyphenyl)phosphine ligand and acetonitrile as solvent, tandem arylation/1,2-alkyl migration from aluminum to carbon affords 7-substituted-1-ethyl-1-methylindanes containing an all-carbon quaternary stereogenic centre in good yields. This reaction is tolerant of 6-aryl methyl ethers, thioethers and trimethylsilanes. Deuterium labeling established that protiodealumination of the key neopentyl(methyl)aluminum triflate intermediate is caused by the acetonitrile solvent. The organodimetallic species in that study were shown to be configurationally stable, hence the stereospecificity of the process that proceeds via carbopalladation, transmetalation and reductive elimination of an alkylpalladium(II) intermediate. When applied to 1-naphthyl triflate-tethered vinylalanes, the same reaction conditions mediate stereospecific 1,2-diarylation, leading to 2,3,3a,4-tetrahydro-1H-cyclopenta[def]phenanthrenes in excellent yields. The influence of DABCO, tether length and solvent polarity was studied. Selective tandem arylation/1,2-methyl migration could also be achieved in non-polar solvent in absence of Lewis base. While steric properties took precedence over electronic considerations when inducing product selection, preagostic C-H···Pd interactions were postulated to facilitate 1,3-metal migration in the production of 1H-cyclopenta[def]phenanthrene derivatives.

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Les analogues de nucléosides ont reçu une attention particulière en raison de leurs importantes applications anticancéreuses et antivirales. Dans cette thèse, de nouveaux analogues nucléosidiques de type 1′,2′-cis et 1′,2′-trans ribo portant un centre stéréogénique quaternaire fonctionnalisé en position C3′ ont été synthétisés par des réactions de N-glycosylation stéréosélectives, qui ont été contrôlées en installant différents types de groupes protecteurs sur le C2′ substituant hydroxyle. Le précurseur acyclique critique de 2,4-syn diol a été obtenu par réduction diastéréosélective d’une β-hydroxycétone en utilisant la délivrance d'hydrure intermoléculaire. Une approche pour une séparation facile des 2,4-syn et 2,4-anti diols par protection/déprotection acétonide a été établie, de sorte que le 2,4-syn diol pur puisse être rapidement accessible par oxydation allylique successive et protection acétonide. Une stratégie alternative a également été développée pour la préparation d'analogues nucléosidiques en C1′-β de type ribo portant un centre quaternaire C3′ avec un groupe hydroxyle C5′ libre. Dans cette stratégie, les diacétates de type ribo ont servi de donneur de glycosyle qui ont été synthétisés à partir d’une époxydation diastéréosélective d’un précurseur de glycal. La réaction énantiosélective consécutive de Mukaiyama aldol et le transfert d'allyle intramoléculaire de radicaux libres catalysé par photoredox ont été établis et développés dans notre laboratoire pour installer le centre stéréogénique quaternaire. Des nucléosides 5′-triphosphates portant soit une purine soit une pyrimidine ont ensuite été synthétisés et sont testés contre le cancer et les infections virales. De plus, l'analogue L-1′,2′-cis-4′-thionucléoside portant un centre quaternaire stéréogénique fonctionnalisé en position C3′ avec un substituant hydroxyle en C2′ a été synthétisé par une stratégie acyclique avec 1′,2′-syn thioaminal précurseur, qui a subi une cyclisation intramoléculaire de type SN2 de type S1′→C4′. Le 1′,2′-syn thioaminal a été synthétisé par une addition de nucléobase diastéréosélective sur un dithioacétal. / Nucleoside analogues have received extensive attention due to their important anticancer and antiviral applications. In this thesis, novel 1′,2′-cis and trans ribo-like nucleoside analogues bearing an all-carbon C3′ quaternary stereogenic center were synthesized using stereoselective N-glycosylation reactions, which were controlled by installing different types of protecting groups on the C2′ hydroxyl substituent. The critical acyclic 2,4-syn diol precursor was obtained by diastereoselective reduction of a β-hydroxy ketone using intermolecular hydride delivery. An approach for easy separation of the 2,4-syn and 2,4-anti diols through acetonide protection/deprotection was established to rapidly access the pure 2,4-syn diol through successive allylic oxidation and acetonide protection. An alternative strategy was also developed for the preparation of ribo-like C1′-β nucleoside analogues bearing an all-carbon C3′ quaternary center with a free C5′ hydroxyl group. In this strategy, ribo-like diacetates served as the glycosyl donors which were synthesized from a diastereoselective epoxidation of a glycal precursor. A consecutive enantioselective Mukaiyama aldol reaction followed by a photoredox catalyzed free radical intramolecular allyl transfer were established and developed in our lab to install the all-carbon quaternary stereogenic center. Nucleoside 5′-triphosphates bearing either a purine or a pyrimidine nucleobase were then synthesized and are currently being tested against cancer and viral infections. In addition, L-1′,2′-cis-4′-thionucleoside analogues bearing an all-carbon C3′ stereogenic quaternary center along with a C2′ hydroxyl substituent were synthesized using an acyclic strategy from a 1′,2′-syn thioaminal precursor followed by a S1′→C4′ intramolecular SN2-like cyclization. The 1′,2′-syn thioaminal was synthesized by a diastereoselective nucleobase addition onto a dithioacetal.