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

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<p>Object rearrangement is a fundamental problem in robotics with various practical applications ranging from managing warehouses to cleaning and organizing home kitchens. While existing research has primarily focused on single-agent solutions, real-world scenarios often require multiple robots to work together on rearrangement tasks. We propose a comprehensive learning-based framework for multi-agent object rearrangement planning, addressing the challenges of task sequencing and path planning in complex environments. The proposed method iteratively selects objects, determines their relocation regions, and pairs them with available robots under kinematic feasibility and task reachability for execution to achieve the target arrangement. Our experiments on a diverse range of environments demonstrate the effectiveness and robustness of the proposed framework. Furthermore, results indicate improved performance in terms of traversal time and success rate compared to baseline approaches. The videos and supplementary material are available at https://sites.google.com/view/maner-supplementary</p>

During the last decades, mitochondria and their DNA have become a hot topic of research due to their essential roles which are necessary for cells survival and pathology. In this study, multiple methods have been developed to help with the understanding of mitochondrial DNA and its evolution. These methods tackle two essential problems in this area: the accurate annotation of protein-coding genes and mitochondrial genome rearrangements. Mitochondrial genome sequences are published nowadays with increasing pace, which creates the need for accurate and fast annotation tools that do not require manual intervention. In this work, an automated pipeline for fast de-novo annotation of mitochondrial protein-coding genes is implemented. The pipeline includes methods for enhancing multiple sequence alignment, detecting frameshifts and building protein profiles guided by phylogeny. The methods are tested on animal mitogenomes available in RefSeq, the comparison with reference annotations highlights the high quality of the produced annotations. Furthermore, the frameshift method predicted a large number of frameshifts, many of which were unknown. Additionally, an eficient partially-local alignment method to investigate genomic rearrangements in mitochondrial genomes is presented in this study. The method is novel and introduces a partially-local dynamic programming algorithm on three sequences around the breakpoint region. Unlike the existing methods which study the rearrangement at the genes order level, this method allows to investigate the rearrangement on the molecular level with nucleotides precision. The algorithm is tested on both artificial data and real mitochondrial genomic sequences. Surprisingly, a large fraction of rearrangements involve the duplication of local sequences. Since the implemented approach only requires relatively short parts of genomic sequence around a breakpoint, it should be applicable to non-mitochondrial studies as well.

An approach to a new class of compounds known as bridgehead dienone is described. The route is based on a tandem contraction-expansion event in which the contraction triggers the expansion. The two steps involved are a palladium-catalyzed Favorskii contraction and a cis-divinyl cyclopropanone rearrangement. Progress towards these goals is reported.

In our previous publication of Thiele cage diols, we describe the first pinacol rearrangement to occur over a C(sp3)–C(sp3). Two mechanisms were initially proposed: a concerted mechanism and a stepwise mechanism, proceeding through a carbocation intermediate. Interestingly, the rearrangement provides only a single diastereomer. The aim of this thesis is to investigate the nature of the reaction by measuring the relative rates of reaction with varying substituents that either stabilize or impede the formation of carbocations. From the relative rates, we can narrow in on whether the mechanism is stepwise or concerted, based on substituent effects, and determine how the reaction may provide a single diastereomer. In Chapter 1, the pinacol rearrangement is introduced, and each analogue that followed after, including stereoselective pinacol rearrangements and a series of different semipinacol rearrangements that provide useful synthetic pathways for chemists with desirable stereochemical outcomes. In Chapter 2, we describe the isolation and characterization of two analogues of a key side product. The structure of each analogue was determined through a series of spectroscopic techniques including 1H-1H COSY, HSQC, HMBC, and 1D-selective gradient NOE NMR. From the solved structures, we proposed a possible mechanism to describe their formation during the main rearrangement reaction – one that shares a carbocation intermediate with the stepwise mechanism already proposed. In Chapter 3, we prepared five Thiele cage diol analogues with aryl substituents with different electronic properties: two substituents that stabilize carbocation intermediates (p-OCH3 and p-CH3), two that destabilize (p-F and 3,5-diOCH3), and the base tetraphenyl Thiele cage diol. We measured the rates of reaction of each diol with p-toluenesulfonic acid at 25°C, 35°C, 45°C, and 52°C via variable temperature quantitative 1H-NMR over time. From the rates of reaction, we found that diols with carbocation-stabilizing aryl substituents reacted faster than the destabilizing analogues, providing evidence that the rearrangement proceeds through a carbocation intermediate. We also found that the diols with electron-deficient aryl substituents showed an increase in the entropy of activation with increasing electron-deficiency in the aryl groups, suggesting an associative pathway for the electron-deficient substituents toward the rearrangement product. Considering the pathway proposed for the side product, we propose an updated stepwise mechanism. Based on computational studies and a previously-isolated X-ray crystal structure, we determined that the diastereoselectivity of the reaction was facilitated by favourable π-π stacking interactions between two aryl substituents. The interaction of the aryl groups twists the geometry of the molecules, placing the migrating aryl substituent in the ideal position for the rearrangement to occur stereoselectively. / Graduate / 2023-10-31

The complementary value of vibrational spectroscopy and mass spectrometry in obtaining structural information on a range of tricyclic indoles with various ring patterns has been investigated, focusing particularly on whether these heterocycles with a functional group containing oxygen in the third ring should be described as ketoindoles or hydroxindolenines. Parallels between certain fragmentations of ionised indoles and electrophilic substitution in solution have been identified. A mechanistically interesting and analytically useful interesting dimerisation, leading to the formation of [2M-H]+ ions, has been discovered in the positive ion electrospray mass spectra of 3-alkylindoles. This dimerisation, which occurs in the nebuliser of the instrument, offers a potential new route to bisindoles under milder conditions than those employed in classical solution chemistry. Facile formation of C=N bonds by condensation of C=O and H2N has been shown to provide a means of preparing protonated imines and protonated quinoxalines from mixtures of the requisite (di)carbonyl compounds and (di)amines, thus further illustrating how organic synthesis is possible in the droplets in the nebuliser of the instrument. Possible metal catalysed coupling reaction routes to bisindoles have been explored. Acyl transfer reactions from nitrogen to carbon have been investigated in 1-acyl-2-methylindoles and orthogonally protected sulphonamides. These processes have been shown to be intermolecular and intramolecular, respectively. The latter rearrangement, which may be prevented when necessary by choosing the nitrophenylsulphonamide protecting group, offers a route to acyl, carboalkoxy and carboaryloxy aromatic compounds, some of which are difficult to prepare.

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