京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第19660号 / 薬科博第48号 / 新制||薬科||6(附属図書館) / 32696 / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 川端 猛夫, 教授 高須 清誠, 教授 竹本 佳司 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第21051号 / 薬科博第94号 / 新制||薬科||10(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 大野 浩章, 教授 竹本 佳司, 教授 高須 清誠 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Thesis advisor: Amir H. Hoveyda / Chapter 1. Catalytic SN2”-Selective and Enantioselective Substitution Reactions. The first broadly applicable strategy for SN2”-selective and enantioselective catalytic allylic substitution will be presented. It will be shown that transformations can be promoted by 5.0 mol% of a sulfonate-containing NHC–Cu complex (NHC = N-heterocyclic carbene), and may be carried out by the use of a commercially available allenyl–B(pin) (pin = pinacolato) or a readily accessible silyl protected propargyl–B(pin). Products bearing a 1,3 diene, a silyl allenyl or a propargyl moiety were obtained in high efficiency and selectivities. Also provided is insight regarding several of the unique mechanistic attributes of the catalytic process, obtained on the basis of kinetic isotope effect measurements and DFT studies. These investigations indicated that cationic π-allyl–Cu complexes are the likely intermediates, clarifying the role of the s-cis and s-trans conformers of the intermediate organocopper species and their impact on E:Z selectivity and enantioselectivity. It will also be shown we were able to highlight the utility of the approach by chemoselective functionalization of various product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products can be converted catalytically and chemoselectively to several synthetically useful derivatives. Chapter 2. NHC–Copper–Hydride-Catalyzed Enantioselective Processes with Allenyl Boronates and its Application in Natural Product Synthesis. Here, the development of a catalytic process that delivers otherwise difficult-to-access organoboron compound will be detailed. These processes involve the combination of a hydride, an allenyl–B(pin) and an allylic phosphate. As will be discussed, two unique selectivity problems were solved: avoiding rapid Cu–H reduction of an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly observed Cu–B exchange. We were able to underscore the considerable utility of the approach by applications to preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and the first enantioselective synthesis of netamine C (anti-tumor), which also served to confirm its stereochemical identity. Chapter 3. Catalytic Enantioselective Prenyl Conjugate Addition Reactions. In this final section, studies leading to the development of the first class of catalytic enantioselective strategies for prenyl conjugate additions will be detailed. At the core of these investigations was finding ways to overcome two problems. One challenge originated from the fact that highly activated allylmetal species often deliver product with low enantioselectivity. The other was that regioselectivity was difficult to control owing to a strong preference for γ-selective additions. As will be described, we were able to address these difficulties by the use of a hydroxy NHC-copper complex and 3,3-dimethyl allyl–B(pin) as a reagent. In the end, we were able to use acyclic as well as cyclic enoates as substrates. The results of DFT studies that provide insight regarding varying selectivity profiles with different chiral ligands will be discussed as well. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

京都大学 / 新制・論文博士 / 博士(工学) / 乙第13456号 / 論工博第4196号 / 新制||工||1770(附属図書館) / (主査)教授 中村 正治, 教授 大江 浩一, 教授 村田 靖次郎 / 学位規則第4条第2項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Thesis advisor: X. Peter Zhang / Highly strained three membered heterocycles are a common motif in many biologically relevant molecules and represent a versatile building block for organic synthesis. Of special interest for asymmetric synthesis is the construction of enantioenriched aziridines and epoxides, which are often used as chiral synthons to introduce heteroatoms in a stereoselective fashion. Among different elegant strategies, the direct aziridination and epoxidation of the ubiquitous alkene functionality represents one of the most powerful methods to access these motifs. Given the synthetic importance of the enantioenriched smallest aza- and oxaheterocycles, the focus of this dissertation is centered on the design and use of chiral cobalt porphyrins as catalysts to develop new methodologies for the asymmetric radical aziridination and epoxidation of alkenes.In the first part of this dissertation, we focused on using carbonyl azides as nitrogen source for the enantioselective radical aziridination of alkenes. Despite its high functionality and versatility for further derivatization, carbonyl azides have never been reported as nitrogen source for intermolecular asymmetric alkene aziridination. In the second part of this dissertation, we focused on opening up a new area of research, which involves the generation and characterization of the unprecedented cobalt porphyrin-supported oxygen-centered radical species. Finally, we demonstrated the synthetic utility of these new radical species by developing a new system for the asymmetric epoxidation of alkenes through the design and development of a novel family of catalyst named “JesuPhyrin”. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Thesis advisor: James P. Morken / Thesis advisor: Marc L. Snapper / This dissertation will present three projects focusing on the enantioselective synthesis and stereospecific transformation of alkylboronates. The first project describes the development of a nickel-catalyzed enantioselective dicarbofunctionalization of alkenylboronates, which provides a modular route to secondary alkylboronic esters. Intramolecular reaction leads to enantioselective synthesis of exocyclic boronates. The second project depicts a new method for the synthesis of azetidines, pyrrolidines and piperidines via an intramolecular amination of alkylboronic esters. Regioselective amination of vicinal bis(boronates) allows the synthesis of saturated azacycles bearing boronic ester substitutions that can serve as useful synthetic handles. As the transformation is stereospecific, stereodefined cyclic amines can be synthesized from the enantioenriched boronic esters. The method is applied to the synthesis of an intermediate towards a Kras G12C inhibitor. The third project describes the development of a new chiral auxiliary on boron that can be easily synthesized from inexpensive starting materials. The auxiliary is applied to a diastereoselective radical ring-opening/closing [3+2] cycloaddition of cyclopropylanilines with alkenylboron species. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Density Functional Theory is used in order to shed light on the reaction mechanisms and the origins of stereoselectivity in enantioselective organocatalytic reactions. The reactions investigated are the dipeptide-catalyzed aldol reaction, the cinchona thiourea-catalyzed nitroaldol reaction and the prolinol derivative-catalyzed hydrophosphination reaction. We can justify the stereoselectivity in the reactions from the energies arising from different interactions in the transition states. The major contributions to the energy differences are found to be hydrogen bond-type attractions and steric repulsions. This knowledge will be useful in the design of improved catalysts as well as general understanding of the basis of selection in other reactions. / QC 20101111

Thesis advisor: James P. Morken / This dissertation presents the development of catalytic enantioselective synthesis and selective functionalization of geminal or vicinal borylsilanes and bis(boronates). In the first chapter, a modular approach to the catalytic synthesis of enantioenriched anti-1,2-borylsilanes will be described, which is enabled by the stereospecific 1,2-metallate shift that occurs during Pd-catalyzed conjunctive cross-coupling reaction. In the second chapter, the Cu-catalyzed site-selective cross-coupling of vicinal bis(boronates) to an array of electrophiles is developed to provide a new method to construct complex boron-containing products from terminal alkenes. A dramatic rate acceleration in transmetalation to copper is enabled by the neighboring activating boronate group in the substrate. Mechanistic experiments suggest that the formation of a chelated cyclic ate complex may play a role in facilitating the transmetalation. As a follow-up project, the site-selective cross-coupling of vicinal diborylsilanes is also investigated. A Pt-catalyzed enantioselective hydrosilylation of (Z)-1,2-diborylethylene provides access to a vicinal 1,2-diboryl-1-silylalkane that can be used in catalytic cross-coupling reactions. Depending on the catalyst employed and the electrophile class, the coupling reaction can occur at either the α or β carbon relative to the silane center. In the last chapter, a practical method is developed to prepare a TiO2 supported gold nanoparticle catalyst that facilitates the cis-diboration of terminal alkynes. The resulting products can undergo a practical Cu-catalyzed site-selective cross-coupling with proton or other non-aryl/alkenyl electrophiles to yield α-substituted alkenyl boronates with excellent yield and site-selectivity. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.