Part 1 - Chapter 1. The goal of the catalysis of 6π electrocyclizations is introduced in the context of known examples of the catalysis of pericyclic reactions. Recent examples of catalytic electrocyclizations and the computational and experimental precedents used to guide our approach are reviewed.

Part 1 - Chapter 2. The acid-catalyzed and thermal cyclization of an isolable vinyl ortho-quinone methide was investigated through DFT calculations and experimental kinetic analysis. We propose that both reactions proceed through rate-limiting exo-alkylidene bond isomerization followed by faster oxa-6π electrocyclization. The vinyl ortho-quinone methide was found to be highly basic, allowing for quantitative protonation with weak acids. In addition, we identified a new mode of Diels-Alder dimerization of vinyl ortho-quinone methides.

Part 1 - Chapter 3. Density functional theory calculations were performed on the coordination of a Lewis acid to a Lewis basic ester substituent at all positions of a hexatriene molecule and the subsequent 6π electrocyclizations of these molecules. These calculations suggested catalysis of the 6π electrocyclization of 2-carbomethoxy-substituted triene substrates is possible. The electrocyclization of hexatriene substrates with a variety of other Lewis basic substituents in the 2-position were modeled in an analogous fashion.

Part 1 - Chapter 4. A 2-carboethoxy-substituted triene substrate was synthesized and catalysis of its electrocyclization using Me2AlCl was demonstrated. Evidence is provided suggesting this reaction proceeds through rapid, reversible, exothermic formation of a catalyst-substrate complex, which then undergoes rate-limiting 6π electrocyclization.

Part 1 - Chapter 5. It was demonstrated that ester, ketone, and amide functionalities are useful Lewis-basic docking groups for the catalysis of 6π electrocyclizations. Catalysis using aldehyde moieties as docking groups was unsuccessful, most likely due to the high reactivity of the aldehyde functional group towards intramolecular nucleophilic attack, as demonstrated by the formation of a novel triene dimer. In one clear example, it was demonstrated that the hexatriene structure must be entropically biased towards electrocyclization in order for catalysis to be successful.

Part 1 - Chapter 6. Moderate levels of enantioselectivity in catalytic 6π electrocyclizations using scandium pyridine-bis-oxazoline catalyst systems were achieved. We have also discovered a catalytic photochemical electrocyclic ring-opening and kinetic resolution of a cyclohexadiene.

Part 2 - Chapter 1. The goal of the depolymerization of lignin via catalytic disproportionation was introduced in the context of the development of a liquid fuel source from this biomass input. The structure, methods of isolation, and methods of industrial and environmental degradation of lignin are introduced. Initial results of the catalytic disproportionation of a lignin model compound of the glycerol-β-aryl ether linkage of lignin as well as literature examples of the types of transfer hydrogenation and carbon-oxygen bond cleavage reactions employed in this system are shown.

Part 2 - Chapter 2. Disproportionation of a 1,3-diol model compound was investigated in order to understand and optimize the retro-aldol cleavage process observed in the disproportionation of a glycerol-β-aryl ether model compound. Evidence is provided suggesting the disproportionation of the 1,3-diol model compound proceeds through rate-limiting retro-aldol cleavage. Also active processes in this reaction are dehydration, carbonyl and olefin hydrogenation, dehydrogenation of formaldehyde, and a water-gas-shift reaction. Early metal and aluminum alkoxides and aryloxides were employed as potent co-catalysts in this disproportionation reaction.

Part 2 - Chapter 3. A number of model systems were employed to investigate the carbon-oxygen bond cleavage processes that are observed in the disproportionation of a glycerol-β-aryl ether model compound. These studies suggest this reaction proceeds through ruthenium-enolate intermediates. Attempts at characterizing the catalyst resting state of the carbon-oxygen bond cleavage reaction via both NMR and IR analysis were unsuccessful. Experiments were performed which suggest the carbon-oxygen bond cleavage of a 2-phenoxy-1-phenylpropenone substrate proceeds through a novel mechanism.

Abstract

sp² Carbon-Hydrogen Bond (C-H) Functionalization

by

Sirilata Yotphan

Doctor of Philosophy in Chemistry

University of California, Berkeley

Professor Robert G. Bergman, Chair

Chapter 1. A review of the Bergman/Ellman group literature on rhodium-catalyzed direct sp² C-H bond functionalization reactions is presented. In addition, some well-known late transition-metal catalyzed sp² C-H bond functionalization reactions are described. These synthetic methods have valuable applications for organic chemistry and enable access to a number of interesting organic compounds and derivatives. These examples highlight the importance of this type of transformation and provide the background from which the results described in Chapters 2-5 may be viewed.

Chapter 2. Bridgehead bicyclic unsaturated enamines were prepared by a tandem rhodium-catalyzed C-H bond activation/alkenylation/electrocyclization of alkyne-tethered unsaturated imines. These strained bicyclic enamines exhibit unique reactivity: for example, they lead to N-alkylated products upon treatment with alkylating reagents and undergo double bond isomerization to alleviate ring strain upon reduction.

Chapter 3. An efficient method is reported for the preparation of multicyclic pyridines and quinolines by a rhodium-catalyzed intramolecular C-H bond functionalization process. The method shows good scope for branched and unbranched alkyl substituents on the pyridine ring and at the R position of the tethered alkene group. Starting materials capable of undergoing olefin isomerization to provide terminal 1,1-disubstituted alkenes also proved to be effective substrates.

Chapter 4. A method for the direct arylation of benzotriazepines is reported, employing an aryl iodide as the coupling partner, copper iodide as the catalyst, and lithium tert-butoxide as the base. A variety of electron-rich, electron-poor, and sterically hindered aryl iodides are compatible with the reaction conditions. The arylation reaction can also be performed outside a glovebox in air without a significant decrease in yield. Furthermore, convenient microwave conditions for carrying out this transformation are reported.

Chapter 5. The reaction of isopropyl Grignard reagent and 3-bromoquinoline leads to formation of interesting 3,4-disubstituted quinoline products in significant yields. This transformation was extensively studied for 3-bromoquinoline as the substrate, isopropyl magnesium chloride as the nucleophile, and a Brønsted acid or 3-bromopropene as electrophiles. A brief survey of this transformation, identification of the reaction limitations, and a suggested mechanism are reported in this Chapter.

Chapter 1. A sequence of research projects beginning with studies in diastereoselective C-H bond functionalization applied to the synthesis of (-)-incarvaillateine to the Rh(III) catalyzed arylation of imines, are described. Some theory and mechanistic considerations are discussed in relation to the genesis of these projects. Research directions are summarized and rationalized.

Chapter 2. The synthesis of (-)-incarvillateine utilizing a key C-H bond alkylation step is described as a means to highlight the synthetic utility of a newly reported olefinic C-H bond functionalization methodology. Elements of diastereoselectivity are also explored in the key step which allows for the concise, stereoselective synthesis of the natural product. Progress in the area of enantioselective C-H alkylations are also summarized as it applies to the synthesis of other natural products.

Chapter 3. A method for the enantioselective cyclization of N-allylimidazoles is developed. The reaction is thought to proceed via a novel, reactive N-heterocyclic carbene. High enantioselectivities are achieved, which is unusual in view of the elevated temperatures of the reaction.

Chapter 4. The first general method for the oxidative coupling of unactivated alkenes via C-H bond functionalization is reported using a methyl oxime directing group. A silver abstractor is important to obtain reactivity. Several functional groups are compatible with the reaction and no precautions to exclude air are required.

Chapter 5. A rare example of C-H activation and intermolecular coupling to N-protected-imines is achieved using a cationic Rh(III) catalyst. The reaction is directed by pyridines and related heterocycles and produces a variety of aryl-branched amines. The reaction accommodates several reactive functional groups and is mild enough to even couple with sensitive alkyl N-sulfonyl-imines.

Abstract

Chapter 1 : Introduction.

Our chemical industry is currently capable of converting fossil fuel feedstocks (unsaturated hydrocarbons) into useful polymers and chemicals. Replacing those feedstocks with renewable sources is an important goal for sustainability. Our research focuses on the defunctionalization of heavily oxygenated biomass materials so they can be used in the chemical industry's current factories. Of particular interest are three and four carbon monomers which would be obtained from the defunctionalization of the simple alditols glycerol and erythritol.

Chapter 2 : Formic Acid-Mediated Didehydroxylation of Vicinal Diols: Reaction Development and Mechanistic Studies

We developed a simple formic acid-mediated didehydroxylation of diols. Our substrate scope was limited to simple polyols. Isotope labeling studies suggested the intermediacy of a carbocation as well as an orthoformate ester. Attempts at isolating the carbocation intermediate were unsuccessful.

Chapter 3 : CO2 Reduction - In situ Formation of Formic Acid with Concomitant Didehydroxylation of Vicinal Diols

We successfully reduced carbon dioxide with a heterogeneous rhodium catalyst to form a mixture of formic acid and amine. Attempts at didehydroxylation using the synthesized mixture were successful, though low yielding. Concomitant reduction of carbon dioxide and didehydroxylation was not achieved.

Chapter 4 : Rhenium-Catalyzed Deoxygenation of Diols and Epoxides

Many oxo-rhenium catalysts were synthesized and used for the deoxygenation of diols and epoxides. We were unable to obtain conclusive spectroscopic data of the reaction's progress, limiting our ability to propose a mechanism.

Synthetic studies of the Thio-Nazarov Cyclization

Biomimetic Total Syntheses of Shimalactones and Exiguamines

Synthesis of Photoswitchable Dopamine Analogs

Vladimir Sofiyev

Doctor of Philosophy in Chemistry

University of California, Berkeley

Professor Dirk Trauner, Co-Chair

Part 1 of this thesis describes progress towards thio-Nazarov electrocyclization utilizing substrates with a removable docking group, such as alkyl sulfides, for Lewis acid coordination. This work builds on the successful asymmetric catalysis of Nazarov electrocyclization using non-removable docking groups for coordination of Lewis acids.

Parts 2 and 3 of this thesis describe the biomimetic syntheses of the natural products shimalactones and exiguamines respectively. While the synthesis of alkaloids exiguamines A and B is an improvement of our previous work, the synthesis of polyketides shimalactones A and B is their first synthesis and describes a novel intramolecular addition of a b-ketolactone across a diene. Both syntheses feature pericyclic reactions in their key step biomimetic cascade reactions.

Part 4 of this thesis describes the synthesis of photoswitchable derivatives of dopamine, containing azobenzenes.

Recently in the Ellman and Bergman groups a method was discovered for preparing 1,2-dihydropyridines via rhodium-catalyzed coupling of α,β-unsaturated imines and alkynes. Subsequent in situ oxidation provides access to the corresponding pyridines. This method was expanded to include terminal alkynes, challenging substrates for transition-metal mediated transformations. In contrast formal reduction of the dihydropyridine intermediates through Diels-Alder reaction with alkenes provides access to isoquinuclidines, an important class of piperidines, in excellent diastereoselectivities.