京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18232号 / 工博第3824号 / 新制||工||1586(附属図書館) / 31090 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 杉野目 道紀, 教授 吉田 潤一, 教授 村上 正浩 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(薬科学) / 乙第13086号 / 論薬科博第2号 / 新制||薬科||9(附属図書館) / (主査)教授 竹本 佳司, 教授 高須 清誠, 教授 川端 猛夫 / 学位規則第4条第2項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20584号 / 工博第4364号 / 新制||工||1678(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 杉野目 道紀, 教授 吉田 潤一, 教授 大江 浩一 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21127号 / 工博第4491号 / 新制||工||1698(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 村上 正浩, 教授 吉田 潤一, 教授 中尾 佳亮 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21776号 / 工博第4593号 / 新制||工||1716(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 中尾 佳亮, 教授 松原 誠二郎, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21796号 / 工博第4613号 / 新制||工||1718(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 村上 正浩, 教授 松田 建児, 教授 中尾 佳亮 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

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The development of new strategies and associated reagents that enable previously inaccessible synthetic disconnections is largely attributing to the remarkable progress in exploring new chemical space for drug discovery and innovative complex molecule syntheses. In the Wengryniuk laboratory, we are devoted to discovering new synthetic methodologies that are based on umpolung or reverse polarity, strategies, enabled by Nitrogen-ligated (bis)cationic hypervalent iodine reagents (N-HVIs). I(III) N-HVIs represent an attractive new class of oxidant as they are environmentally benign, highly tunable, and have shown ability in enabling distinguished modes of reactivity. This dissertation focuses on demonstrating the synthetic utility of these N-HVI reagents towards C–O bond formation via a reverse polarity approach.In Chapter 1, a summary of the reactivity and characteristics of hypervalent iodine reagents is provided. Chapter 2 describes a mild and metal-free strategy for alcohol oxidation mediated by I(III) N-HVI reagents. This method demonstrates the first method for chemoselective oxidation of equatorial over axial alcohols and was the first in situ synthesis and application of N-HVIs for a simple one-pot procedure. Chapter 3 discusses a novel strategy for a dual C–H functionalization to access functionalized chroman scaffolds via an umpolung oxygen activation cyclization cascade. Computational studies in collaboration with Prof. Dean Tantillo (UC-Davis) along with experimental probes in our laboratory, support the formation of an umpoled oxygen intermediate as well as competitive direct and spirocyclization pathways for the key C–O bond forming event. The utility of the developed method is demonstrated through a downstream derivatization of the iodonium salt moiety to access C–H, C–X, and C–C substitution via established Pd-catalyzed cross couplings. Total synthesis of (±)-conicol natural product was performed in 8 steps and 23% overall yield, further demonstrating the synthetic utility of the developed method. Key synthetic steps include a smooth construction of the chroman core via N-HVI mediated C–H etherification of a pendant alcohol followed by a late-stage double bond installation. Overall, this dissertation summarizes the current state of research enabled by N-HVI reagents, with a focus on their utility in reverse polarity heteroatom activation strategies, and it serves as a practical guide for future development in the field. / Chemistry

Nitrogen is a vital element for the existence of life, as shown by its frequent presence in essential biomolecules, and inclusion into valuable drugs. Sulfonamides and their heterocycle counterpart, sultams, are N-containing functional groups and metabolically stable amide isosteres. Sulfa drugs, which contain these moieties, have a broad spectrum of medical applications. The industrial value of sultams has prompted the development of novel methods for their synthesis, and metal-catalyzed C-H amination reactions with nitrene precursors have recently shown promise. The current thesis presents a survey of conditions for benzo[d]sultam synthesis via intramolecular C-H amination of N-acyloxysulfonamides. Initially, using Ru(Bpy)3(PF6)2 as a photocatalyst and Et3N as a base enabled benzo[d]sultam formation by tertiary C-H amidation. The photoredox conditions were optimized to accommodate other 2,6-disubstituted-N-acyloxysulfonamides upon omission of the base, which consistently gave sulfonamide byproducts. Control reactions indicated that a thermal base-induced reaction was simultaneously occurring, both enabling productive C-H amidation and byproduct formation. Systematic optimization of base-induced conditions enabled sultam synthesis from 2,6-dialkyl- and tertiary ortho-monoalkyl-precursors in moderate yield, but sulfonamide formation still impeded the reaction.   An additional control reaction indicated that a thermal Ruthenium-catalyzed C-H amidation reaction was possible. Indeed, heating N-acyloxysulfonamides in the presence of Ru(Bpy)3(PF6)2 and in the absence of light and base enabled efficient C-H amidation, particularly with DCE as a solvent. A representative scope of 12 benzo[d]sultams was then synthesized including entries derived from ortho-monoalkyl-N-acyloxyarylsulfonamides. Aside from optimizing an efficient reaction for the synthesis of benzo[d]sultams through the cyclization of N-acyloxyarylsulfonamides, including the challenging primary C-H amidation of orthomonomethyl-substrates, the unique reaction conditions developed in this thesis set precedent for future investigation of hydroxylamine derived nitrene precursors. The optimization and design of superior ruthenium catalysts could allow for more challenging C-H amination reactions with hydroxysulfonamide derivatives and similar N-oxy nitrene precursors.

<p>  </p> <p>Alkyl radicals are powerful intermediates for the generation of carbon-carbon bonds, which play an indispensable role in the synthesis of natural products, pharmaceuticals, and pesticides. Traditionally, there are two main methods for the generation of alkyl radicals. The first is C-H bond functionalization via hydrogen-atom-transfer (HAT). HAT processes have been used as an effective approach for selectively activating C-H bonds via radical pathways. The other strategy to explore the generation of alkyl radicals is C-X bond functionalization via halogen-atom-transfer (XAT). Alkyl halides are one of the largest classes of building blocks in synthesis and they can be obtained from the corresponding alcohols. The most straightforward and effective way to form such alkyl radicals is the direct homolytic cleavage of C-X bonds. In past decades, photoredox catalysis has emerged as a powerful and greener tool for the synthesis of radicals under mild reaction conditions, which has brought tremendous attention. Although remarkable success has been made in this field, some methods still require costly transition metal catalysts or toxic reagents. Herein, we display a series of visible light-induced approaches under transition-metal free conditions or using earth-abundant metals. These novel photo-induced transformations and corresponding mechanistic work will be discussed in the following order:</p> <p>We will first present our work on metal-free visible-light-promoted C(sp3)-H functionalization of aliphatic cyclic ethers using trace O2.  This reaction uses a trace amount of aerobic oxygen as the sole green oxidant under blue light at room temperature to achieve the synthesis of sulfone and phosphate derivatives in good to excellent yields using cyclic ethers and vinyl sulfones. Then, we report on a photo-induced C(sp3)-H chalcogenation of amide derivatives and ethers via a ligand-to-metal charge-transfer. This reaction converts secondary and tertiary amides, sulfonamides, and carbamates into the corresponding amido-<em>N,S</em>-acetal derivatives in good yields, using an earth abundant metal catalyst under mild conditions.</p> <p>Finally, we present a photoredox polyfluoroarylation of alkyl halides via halogen atom transfer. This method converts primary, secondary, and tertiary unactivated abundant alkyl halides into the corresponding polyfluoroaryl compounds in good yields and has good functional group compatibility.</p>