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Ansamycin natural products have historically been a rich source of new drugs for the treatment of bacterial infections and cancer. The C17-benzene ansamycins in particular have shown excellent preclinical results as potential anti-fungal and anti-cancer medicines. However, their thorough clinical evaluation has been hampered by the absence of a concise synthetic strategy. In order to address this issue, recently developed hydrogenative carbon-carbon bond forming methods were applied toward a short total synthesis of C17-benzene ansamycins. This class of natural products provides a challenging testing ground for these methods while facilitating the further development of compounds which may be used as treatments for life threatening diseases. In the first synthetic approach to the C17-benzene ansamycins key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core. The second approach toward triene-containing C17-benzene ansamycins resulted in the syntheses of trienomycins A and F, which were prepared in 16 steps (longest linear sequence) and 28 total steps. The C11-C13 stereotriad was generated via enantioselective ruthenium-catalyzed alcohol CH syn crotylation followed by chelation-controlled carbonyl dienylation. Finally, diene-diene ring closing metathesis to form the macrocycle. The present approach is 14 steps shorter (LLS) than the prior syntheses of trienomycins A and F, and eight steps shorter than any prior synthesis of a triene-containing C17-benzene ansamycin. / text

The work described in this thesis documents the development of new rhodium(I)-catalysed methodologies within two areas of research. The first examines the use of carbonyls as chelating groups in hydroacylation to produce synthetically valuable ketones and enones. The second area explores new carbon-carbon bond activation methodologies. Chapter 1 presents a literature review of the historical development of rhodium-catalysed hydroacylation, with a focus on chelating groups that can currently be used to suppress decarbonylation. A brief review of methodologies that avoid the requirement for a tether is also included. Chapter 2 describes the development of a novel hydroacylation methodology employing carbonyl-based functional groups as tethers on aldehyde substrates. The chapter begins with the optimisation studies for the hydroacylation of β-formyl amides with terminal and internal alkynes, allenes and terminal alkenes, and subsequently explores the substrate scope for each case. The chapter then outlines the investigations undertaken with 1,4-dicarbonyl and 1,5-dicarbonyl systems, N-formyl amides, β-formyl esters and finally β-formyl ketones. A detailed description of the routes undertaken to synthesise each starting material is also presented. Chapter 3 presents a short review surveying the key milestones in the development of carbon-carbon activation methodologies. The chapter begins with a theoretical comparison to carbon-hydrogen activation and a discussion of the unique challenges that are faced. An overview of the major strategies employed to enact these processes is subsequently presented for both strained and unstrained substrates. Chapter 4 outlines the attempts undertaken to develop a novel carbon-carbon bond activation methodology. The work evaluates sulfur-, nitrogen- and alkene-based chelating groups, known to be successful in hydroacylation, in analogous ketone substrates. Chapter 5 discusses the conclusions from this work and the potential for further work. Chapter 6 presents the experimental procedures and data.

Within the last few years, a significant contribution to the discovery of sp2C−H activation processes and useful applications for cross-coupling C−C bond formation has been achieved by the use of ruthenium(II) arene catalysts. The aim of this thesis is to describe a modular approach for the synthesis of several ruthenium(II) arene complexes with the potential for C−H activation. Another cutting-edge field, catalytic enantioselective functionalization of C−H bonds by transitional metal catalysts, has also been realized within the last few years. It represents a highly atom- and step-economic approach toward the generation of structural complexity. However, the majority of current methodologies rely on the usage of late third- row transition metals such as pallidum, iridium and rhodium. There is a need that motivates the search for cheaper, relative earth abundant metals that could have similar catalytic ability. Herein is also represented a preliminary study of a ruthenium(II)-catalyzed enantioselective access to chromane moiety enabled by chiral transient directing group.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第25138号 / 理博第5045号 / 新制||理||1719(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 依光 英樹, 教授 畠山 琢次, 教授 松永 茂樹 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

In Michael J. Krische research group we are developing new transition metal catalyzed Carbon-Carbon (C-C) forming reactions focusing on atom economy and byproduct free, environmental friendly approaches. We have developed a broad family of C-C bond forming hydrogenations with relative and absolute stereocontrol which provide an alternative to stoichiometric organometallic reagents in certain carbonyl and imine additions. Inspiring from the group work my goal was to develop new reactions, extend the scope of our group chemistry and their application towards synthesis of biologically active natural products. I have been part of enantioselective Rh catalyzed Aldol reaction of vinyl ketones to different aldehydes. Also, we have found that iridium catalyzed transfer hydrogenation of allylic acetates in the presence of aldehydes or alcohols results in highly enantioselective carbonyl allylation under the conditions of transfer hydrogenative. Based on this reactivity a concise enantio- and diastereoselective synthesis of 1,3-polyols was achieved via iterative chain elongation and bidirectional iterative asymmetric allylation was performed, which enables the rapid assembly of 1,3-polyol substructures with exceptional levels of stereocontrol. The utility of this approach stems from the ability to avoid the use of chirally modified allylmetal reagents, which require multistep preparation, and the ability to perform chain elongation directly from the alcohol oxidation level. This approach was utilized for the total synthesis of (+)-Roxaticin from 1,3-propanediol in 20 longest linear steps and a total number of 29 manipulations. Further, advancements were made in iridium catalyzed C-C bond formation under transfer hydrogenation. While methallyl acetate does not serve as an efficient allyl donor, the use of more reactive leaving group in methallyl chloride compensate for the shorter lifetime of the more highly substituted olefin π-complex. Based on this insight into the requirements of the catalytic process, highly enantioselective Grignard-Nozaki-Hiyama methallylation is achieved from the alcohol or aldehyde oxidation levels. Also, a catalytic method for enantioselective vinylogous Reformatsky- type aldol addition was developed in which asymmetric carbonyl addition occurs with equal facility from the alcohol or aldehyde oxidation level. Good to excellent levels of regioselectivity and uniformly high levels of enantioselectivity were observed across a range of alcohols and aldehydes. / text

The non-sustainable nature of fossil fuels as feedstocks for valuable chemicals, combined with the environmental damage caused by their extraction and combustion, increases the need for the development of a bio-based economy. While industry and public opinion are slowly shifting towards acceptance of this change, efficient technologies for the depolymerization and subsequent separation of lignocellulosic biomass fall short of the ever-increasing demand. In particular, there are currently no efficient, sustainable mass scale methods to convert lignin, the most abundant source of aromatic molecules on Earth. The use of oxovanadium(V) catalyst complexes to aerobically cleave C‒C bonds has been demonstrated previously and remains an attractive option for incorporation into a sustainable bio-based economy. Two new triphenoxyamine oxovanadium(V) catalysts with reduced steric bulk and electron density at the metal center (vs. previously reported complexes) have been synthesized for aerobic oxidative diol C‒C bond cleavage. These complexes were found to cleave less activated and more complex substrates than previous generations, including cyclic diols and polyalcohols. Several insights into the reaction pathways of this class of complex were elucidated through a series of kinetic studies. Experimentally, the rate of C‒C bond cleavage of both pinacol and hydrobenzoin was determined to be unaffected by substitution of the O‒H bonds with deuterium, suggesting that currently proposed mechanisms need to be revised. Multiple catalytic regimes were observed during anaerobic reaction, which were not altered significantly by the brief addition of O2. A series of density functional theory calculations revealed a plausible mechanism for the trialkoxy complex that did not involve a proton transfer in the rate determining step, instead suggesting that ligand-arm dissociation-reassociation play a significant role in the reaction. In a second project, new bisphenoxyamine-N-appended base ligand with less steric hindrance and electron density at the metal center, has been synthesized utilizing similar design principles gained from work with triphenoxyamine catalysts. When reacting with lignin model compound 1,2-diphenyl-2-methoxyethanol, this new complex displays a higher selectivity towards aldehydes and esters (relative to previous bisphenoxyamine-N-appended ligands), leading to a higher rate of C‒C bond cleavage. Investigations into the mechanism of bisphenoxy complexes, as well as the role of the N-appended base in reactivity, were performed using substrate pre-complexed bisphenoxy compounds. Thermolysis at 60 and 100 °C produced almost exclusively oxidative C‒H bond cleavage product benzyl methyl ether, with evidence for overoxidation product benzoic acid observed. Thermolysis of labelled substrate pre-complexed revealed that N-appended base may impede C‒C cleavage of 1,2-diphenyl-2-methoxyethanol by forcing the methyl ether away from the oxovanadium(V) center. Through the use of these multidentate phenoxyamine ligands, advances have been made towards sustainable oxovanadium catalysis in the pursuit of efficient and selective lignocellulosic disassembly for a sustainable bio-based economy.

This thesis describes the development and mechanistic studies of carbocyclization reactions of allene-substituted olefins and 1,3-dienes, catalyzed by palladium(0) and palladium(II). These reactions results in the formation of [n,3,0] bicyclic systems (n = 3-5) with high stereoselectivity and in good to excellent yields. The first carbocyclization presented is a novel palladium(0)-catalyzed cyclo- isomerization of allene-substituted olefins. Secondly an efficient aerobic biomimetic system has been developed for a Pd(II)-catalyzed allylic oxidative carbocyclization of allene-substituted olefins. Additionally, during the studies of palladium-catalyzed carbocyclizations of allene-substituted olefins, it was found that in the absence of palladium a mild thermal ene-reaction occurs. In this manner stereodefined, functionalized bicyclic compounds are obtained with good regioselectivity and in high yields. The third and fourth carbocyclization developed are a palladium(II)-catalyzed oxidation and a palladium(0)-catalyzed intramolecular telomerization of allene-substituted 1,3-dienes. A mechanistic study of the palladium(II)-catalyzed oxidation of allene-substituted 1,3-dienes was made, and reaction intermediates could be isolated. The stereochemistry of the reaction intermediates was assigned, and this made it possible to suggest a mechanism for the reaction. The presented mechanism is a trans carbopalladation of the 1,3-diene, where the allene act as the carbon nucleophile. Due to different stereochemical outcomes of the stoichiometric and catalytic reactions, this mechanism could only explain the stoichiometric reaction. Another mechanism for the catalytic reaction was suggested, which rationalizes both the regio- and stereochemistry of the products.

N-phenylpyridin-2-amine , treated with stochiometric amount of palladium(II) acetate in dichloromethane at 65-70¢J for 4 h, to give high yield palladacycle 53. The reaction of palladacycle 53 with potassium aryltrifluoroborates in 1,4-dioxane at 140¢J for 24 h, could give a variety of N-(2-pyridinyl)carbazoles 55a-55m via sequential C-H bond activation. Carbazole derivative 55a reacted with irdium chloride gave iridium dimer, which followed by addition of picolinic acid via ligand exchange will form iridium complexes, which can further be utilized as OLEDs materials.

Under the conditions of transfer hydrogenation utilizing chromatographically purified ortho-cyclometallated iridium C,O-benzoate precatalysts, enantioselective carbonyl crotylation and methallylation can be performed in the absence of stoichiometric metallic reagents and stoichiometric chiral modifiers. In the case of carbonyl crotylation, use of a preformed precatalyst rather than an in situ generated catalyst results in lower reaction temperatures, providing generally higher diastereoselectivity and yields. By utilizing a more reactive leaving group in chloride over acetate on our methallyl donor, the inherently shorter lifetime of the olefin π-complex is compensated for, giving our group’s first report of reactivity utilizing 1,1-disubstituted allyl donors. / text