京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21779号 / 工博第4596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 松原 誠二郎, 教授 中尾 佳亮, 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

Potassium permanganate oxidations and novel cycloaddition chemistry of the arene-cis-diols (7) were investigated. It was found that permanganate oxidation of arene-cis-diols yielded a mixture of 2 products, (157a) and (157b) in low yield. The influence of the C1-substituent on the outcome of the reaction was found to be a complex mixture of steric and electronic effects. In the area of cycloaddition chemistry of protected (7), this thesis describes novel [4+2] cycloadditions with quinones along with the first published report of benzyne and nitrile oxide cycloadditions of these homochiral molecules. The structure of the cycloadducts were elucidated by nOe as well as 2D-NMR analysis and were supported by Frontier Molecular Orbital theory. Finally, arene-trans-diols (200) were synthesized from (7) by a multistep stereoselective protection/deprotection sequence utilizing the Diels-Alder reaction. These compounds serve as intermediates in an approach to the amaryllidaceae alkaloid (+)-pancratistatin (12). / Ph. D.

All four monosubstituted halobenzenes Sa-d have been converted to the corresponding cis-arenediols by a microbial oxidation with the bacterium Pseudomonas putida strain 39- D. Enantiomerically pure cis-diols were obtained from chloro- and bromobenzene. The acetonides of these two diols have been utilized as useful synthons in the preparation of several natural products, like conduritols E 1 and F 2, aminoconduritol A-1 3 and lycoricidine 4. The optical purity of bromocyclohexadienediol, was determined by its conversion to three different natural products ((+)-conduritol E 1, (-)-conduritol F 2, and (+)- aminoconduritol A-1 3), and compared with their optical rotation. Several dienophiles were added to the protected cis-arenediols to study the regio- and stereochemistry of the cycloaddition. The addition of dienophiles to the acetonide of the diols was anti in every case. When ethyl propiolate was used, two regioisomers 7 and 8 were obtained. In contrast, the addition of nitroso dienophiles, derived in situ from the oxidation of hydroxamic acids, to protected halocyclohexadienediols provided chiral bicyclic oxazines of type 9, as single isomers. These compounds were converted by reductive cleavage to 1,4-hydroxy amides. The anti-addition to the acetonide and the stereospecific formation of the two new chiral centers adjacent to the acetonide was exploited in an approach to a more complex phenanthrene natural product lycoricidine 4. / Ph. D.

A novel acid-catalyzed self-condensation reaction of 6-diketones in the presence of 2,2,2-trifluorodiazoethane (TFD) has been discovered. This reaction is of interest because not many methods are available for the preparation of cyclized products (e.g., aromatic natural products) from 6-dicarbonyl units. Acid-catalyzed reactions of 1-phenyl-1,3-butanedione and several substituted derivatives of 1- phenyl-1,3-butanedione with TFD afforded two groups of substituted biphenyl compounds. One of these groups could be an important synthon for the preparation of larger polycyclic aromatic compounds. Several cyclized products have also been obtained from the reaction of 2, 4-pentanedione with TFD. Two potential mechanisms have been suggested to describe this cyclization process. Mechanistic studies utilizing dienophiles suggest that the previously described cyclized products have originated from Michael addition reactions. Several NMR techniques have been utilized to characterize the reaction products which were obtained in this study. These techniques include ¹³C labeling, the ¹³C NMR INADEQUATE pulse experiment, and applications of lanthanide shift reagents. The results that were obtained from the lanthanide shift reagent studies illustrate that certain oxygen atoms can be converted to 2, 2, 2-trifluoroethyl ethers to prevent complexation with lanthanide shift reagents. This methodology was successfully utilized to simplify the interpretation of lanthanide shift reagent results that were obtained from polyfunctional molecules. The reactions of several additional β-diketones have also been studied to better understand the cyclization process. / Ph. D.

The behaviour of chiral 1,3-dioxolan-4-ones, derived from reaction of mandelic and lactic acid with pivalaldehyde, as chiral acyl anion equivalents has been examined. Addition of the corresponding 5-anions to a substituted nitrostyrene and to butenolide was achieved and the structure and stereochemistry of the adducts established by X-ray crystallography. Fragmentation under flash vacuum pyrolysis (FVP) conditions occurred in the expected way (loss of Bu([superscript]t)CHO and CO) in the latter case, but in the former reductive cyclisation was used to generate functionalised lactams. An unexpected reaction of a dioxolanone anion with the dioxolanone to afford an aldol-like dimer was observed in one case. Attempts to extend the range of dioxolanones by using amino acid-derived α-hydroxy acids met with limited success. Only the 5-benzyl compound derived from phenylalanine was obtained in reasonable yield and an attempt to alkylate it led again to aldol-like dimerisation. Cycloaddition to the double bond of 2-t-butyl-5-methylene-1,3-dioxolan-4-one was used to gain access to a range of novel spiro bicyclic and polycyclic systems and fragmentation of these was expected to provide products resulting from a chiral ketene equivalent. While the epoxide derived from the cyclopentadiene Diels Alder adduct did behave in this way to give the chiral ketone in high e.e., the corresponding aziridine underwent unexpected isomerisation pointing to a stepwise fragmentation mechanism of possible general applicability in these systems. Adducts were also formed with tetracyclone and 1,3-diphenylisobenzofuran and an interesting pattern of exo/endo selectivity was observed in these cases. With tetrachlorothiophene dioxide the adduct again fragmented in an unexpected way to give tetrachlorobenzoic acid, providing further support for the intermediacy of an oxonium carboxylate species. 1,3-Dipolar cycloaddition to 2-t-butyl-5-methylene-1,3-dioxolan-4-one was achieved for the first time and a range of adducts containing novel spiro heterocyclic ring systems derived from nitrile oxides, nitrones and diazo compounds were obtained and characterised. The regiochemistry of addition as well as the relative and absolute stereochemistry was demonstrated by X-ray structures of three adducts. Upon pyrolysis some of these compounds unexpectedly lost Bu([superscript]t)CHO and CO2 to give carbene-derived products, including a β-lactam in one case. Cycloaddition reactions of the achiral 2,2-dimethyl-5-methylene-1,3-dioxolan-4-one were also briefly studied.

Tetrahydrofuran (THF) and tetrahydropyran (THP) rings are commonly found in a wide range of natural products and biologically active compounds. In total synthesis, the formation of THF/THP motifs is often the key step but existing methods often involve numerous steps and low overall efficiencies. Part one of this thesis details the development of a practical method for the synthesis of THF rings by the controlled mono-addition/cyclisation of organolithium species to C2-symmetric diepoxides (Scheme A-1). This method can also be applied to the synthesis of bis-THF rings from triepoxides and has potential applications in more complex cascade reactions. A similar cyclisation process providing THF rings from epoxyaldehydes is also described. Part two of this thesis details our efforts towards the synthesis of the marine macrolide neopeltolide. Wright and co-workers reported the isolation of neopeltolide 211 from a deep-water sponge of the family neopeltidae off the north coast of Jamaica. The structure, which was assigned by NMR and HRMS studies and reassigned by total synthesis, contains a 14-membered macrolactone, a 2,6-cis THP ring and an unsaturated oxazole side-chain. Chapter four describes the synthesis of the C2-C8 and C9-C16 fragments (Scheme A-2). Chapter five details our initial attempts in the coupling of subunits 268 and 320, as well as a revised synthetic strategy that allowed us to successfully couple C2-C9 alkyne 347 with C10-C16 aldehyde 348 and the preparation of an advanced intermediate 364 (Scheme A-3).

The synthesis of E- and Z-1,1,2,3-tetramethylsilacyclobutanes is described. Pyrolysis of either isomer at 398.2 °C provides the same products but in different amounts: propene, E- and Z-2-butene, allylethyldimethylsilane, dimethylpropylsilane, the respective geometric isomers, 1,1,2,3,3-pentamethyl-1,3-disilacyclobutane, 1,1, l-ethyldimethyl-2,2,2-vinyldimethyl-disilane and E- and Z-1,1,2,3,3,4-hexamethyl-1,3-disilacyclobutane. Mechanisms involving di- and trimethylsilenes are described for disilane formation and rate constants of the elementary steps for the fragmentation reactions are reported. Photochemically generated dimethylsilylene in the hydrocarbon solution inserts into the cyclic Ge-C or Si-C bonds of 1,1-dimethylgerma- or silacyclobutane to produce 1-germa-2-sila- or 1,2-disilacyclopentane. The relative reactivities of 1,1-dimethylgerma- and silacyclobutanes toward the dimethylsilylene have been determined. The carbenoid resulting from the cuprous chloride catalyzed decomposition of diazomethane at 25 °C in cyclohexane reacts with 1,1-dimethylgermacyclobutane to give, surprisingly 1,1,5,5-tetramethyl-1,5-digermacyclooctane as the major product. The reactions of the carbenoid with 1,1-dimethylsilacyclobutane are described. The kinetics of gas phase thermal decomposition of 1,1-dimethylgermacyclobutane has been studied over the temperature range, 684 - 751 K at pressures near 14 Torr. The Arrhenius parameters for the formation of ethylene are k_1 (s^-1) = 10^(14.6 ± 0.3) exp (62.7 ± 2.9 kcal mol^-1/RT) and those for the formation of propene and cyclopropane are k_2 (s^-1) = 10^(14.0 ± 0.1 ) exp (60.4 ± 2.8 kcal mol^-1/RT). Static gas phase pyrolyses of 1,1-dimethyl-lsilacyclobutene, DMSCB, in the presence of a variety of alkenes and alkynes at 260 - 365 °C have been studied. Our experimental results suggest that under these conditions the DMSCB ring opens to 1,1-dimethyl-l-silabutadiene, which either recyclizes to DMSCB or reacts with alkenes or alkynes in competing 4 + 2 and 2 + 2 cycloadditions.

Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient cyclobutane. The novel tandem intramolecular photocycloaddition- retro-Mannich (TIPCARM) sequence leads to a spiropyrrolidine which is poised to undergo a second retro-Mannich fragmentation [TIPCA(RM)₂] that expels the malonate unit present in the photo substrate and generates transiently an indolenine. The indolenine undergoes rearrangement to a β-carboline which can undergo further rearrangement under oxidizing conditions to an oxindole. Three oxindole natural products, coerulescine, horsfiline and elacomine, were synthesized using this strategy. The TIPCARM strategy was extended to an approach that would encompass the Vinca alkaloids vindorosine and minovine. In this case, the TIPCARM sequence was followed by an intramolecular cyclization that provided tetracyclic ketone 5.86 containing rings A, B, C and D of vindorosine. A tetracyclic intermediate was synthesized which could also provided access to the Vinca alkaloid minovine. / Graduation date: 2012

The thesis entitled "Structure and reactivity in bridged polycyclic systems: cis-trans enantiomerism, fulvene cycloadditions and crystallographic studies of bridgehead β-ketoacids " consists of two parts. Part I contains 3 chapters, and deals with cycloaddition reactions of 6-arylfulvenes with maleic anhydride and nitrones (The products in the case of maleic anhydride display cis-trans enantiomerism). Part II contains 2 chapters, and deals with resolution of racemic primary amines, racemic amino acids and the relative decarboxylation propensities of bicyclic β-ketoacids in solid state. Part I Chapter 1: A new case of the uncommon cis-trans enantiomerism is presented in the Diels-Alder cycloadducts (3 & 4) of 6-arylfulvenes (1) with maleic anhydride (2).1 The resolution of the cis-trans enantiomers were accomplished via the formation of diastereomeric imides 6 and 7 with (1S)-(naphth-1-yl)ethylamine (5), and their subsequent hydrolysis and recyclisation (Scheme 1). The enantiomers 3 and 4 were characterized spectrally, polarimetrically (including CD) and by chiral HPLC. The chiral anhydrides were also stereospecifically converted to the corresponding imides by treatment with aq. ammonia in excellent yields. The crystal structure of one of the diastereomeric imides (derived from 6-phenylfulvene) was determined, and based on the known S configuration of the naphthylethylamine moiety, the configurations of the original anhydride adducts could be assigned.2 Scheme 1 Chapter 2: In this chapter tricyclic imides (8a-c) were prepared by Diels-Alder reaction of 6-arylfulvenes (1a-c) and maleic anhydride (2),2 followed by treatment with aq. NH3. The exo isomers were found to exist as conglomerates when the aryl group was p-tolyl or p-anisyl (although not phenyl). Triage of the p-tolyl racemate (Scheme 2), followed by reaction with p-toluenesulphonyl chloride in CH2Cl2/Et3N, led to the crystalline enantiopure N-tosylimides 9 (These were also found to be conglomerates). X-ray diffraction analysis of the N-tosylimides (9) via the anomalous dispersion technique led to the assignment of the absolute configurations (as either E or Z).3, 4 The original p-tolyl imide enantiomers were found to racemise upon UV irradiation in CHCl3. Based on this, a possible second order asymmetric transformation under photochemical conditions was attempted, and indeed led to the isolation of crystalline imide with a small ee (~15%).5 Scheme 2 Chapter 3: This chapter deals with the fulvene-nitrone cycloadditions. The possibility of discovering examples of the rare (6π + 4π) cycloaddition prompted an exploration of the reaction between electron-rich nitrones and pentafulvenes. In previous reports of such cycloadditions, diazomethane or benzonitrile oxide was used as 4π component.6 Building on previous work from this laboratory,7 the reaction between a set of substituted fulvenes and electron rich nitrones were studied. Theoretical calculations indicate that the (6π + 4π) mode would be favored when the fulvene-nitrone cycloaddition is controlled by the LUMO (fulvene) – HOMO (nitrones) interaction.8 Electron withdrawing groups on the fulvene would lower the LUMO and facilitate the above orbital interaction. Therefore the reaction between electron poor fulvenes and nitrones was taken up for further study. In particular, fulvene (10) was reacted with nitrones (11). However, only a (2π + 4π) mode was observed, involving one of the endocyclic double bond of the fulvene, in moderate yields (Scheme 3). Structures of these adducts were assigned based on NMR and X-ray crystal structure determination. The failure to observe the (6π + 4π) mode (14) is intriguing, and it is not clear whether this is due to electronic or steric reason. Scheme 3 Part II Chapter 1 describes the resolution of racemic primary amines and racemic amino acids (16) via the formation of diastereomeric imides. For this purpose D-camphoric anhydride (15) was chosen as the chiral auxiliary for the following reasons: it is of low-molecular weight with a rigid backbone, and is also easily prepared and purified.9 Primary amine (16) was treated with D-camphoric anhydride (15) in presence of CHCl3/DCC to form the corresponding diastereomeric imides 17 and 18. (In the case of amino acids, the corresponding methyl esters were treated with D-camphoric anhydride (15) in presence of triethylamine in chloroform). The resulting diastereomeric imides 17 and 18 were separated by silica gel column chromatography (Scheme 4), and hydrolyzed to the chiral amines (or amino acids). (The by-produced camphoric acid could be reconverted to D-camphoric anhydride (15). Scheme 4 Chapter 2: The relative ease with which β-ketoacids tend to lose CO2 is intriguing and has been the focus of numerous mechanistic studies.10-12 It is generally believed that the decarboxylation of β-ketoacids occurs via a six-centered hydrogen bonded transition state (19), which leads to the formation of the enol tautomer (20) of the final ketone product (Scheme 5). Scheme 5 Scheme 6 The initial formation of the enol is apparently supported by the high thermal stability of bicyclic β-ketoacids, in which the carboxylic acid functionality is at bridgehead. In these the formation of the enol would be disfavored by Bredt’s rule, which forbids the formation of a double bond at the bridgehead (particularly in the smaller bicyclic compounds). Also, it may be expected that these trends would be manifested in the ground state. This is because there would be a stereoelectronic requirement for the decarboxylation reaction, by which the bond to the carboxylic group would need to be parallel to the C=O π bond of the keto group. Therefore, it was of interest to study the crystal structures of suitable β-ketoacids in the hope of evidencing the above structural trends (Structure for the analogs 21-23 have been reported previously (Scheme 6)).13-15 In fact, the approach pioneered by Dunitz was of particular interest in this regard. 16 In this approach crystal structures of a series of analogs were studied; these analogs possess varying degrees of strain that could be considered as leading to the transition state of a certain reaction. The bond length and related data are then employed to ‘map’ the reaction dynamics. Compound Bond* lengths (Å) Increase in the bond length compared to ketopinic acid (%) Decarboxylation temp.17 * fine bond at the bridgehead to the COOH group. In the case of the decarboxylation of β-ketoacids, a correlation between the lengthening of the bond to the COOH group and the ease of decarboxylation was sought. Therefore the set of analogs 24-26 were prepared (Scheme 6) and their crystal structures determined by X-ray diffraction (at 100K). In the case of 26, an increase of 2.47% relative to 21 in the Cα-COOH bond length was observed. However, no evidence for an intramolecular O=C-O-H…O=C H-bonding, was observed in the crystal structures of 24-26. Instead, the COOH moieties were seen to participate in intermolecular O-H…O hydrogen bonding via the well known carboxylic acid dimer motif. The β-ketoacids were also converted into their corresponding S-benzylisothiouronium salts (Scheme 6), to study the effect of destroying the COOH dimer motif. The salts 27 and 28 could be obtained in a form suitable for single crystal X-ray diffraction. The crystal structures revealed an increase in the Cα-COO- bond length to an extent of 1.97% in case of 28 relative to 27. Also, there is an increase in the relevant bond length of ~0.8% on going from 24 (m.p. 145 °C) to 26 (m.p. 132 °C). Note also that these compounds melts with decompositions. Therefore, it appears that the ease of decarboxylation of these analogs is reflected in the relative lengthening of the bond to the COOH group. Thus, this study represents an application of the Dunitz crystallographic approach to reaction dynamics,16 to the case of the decarboxylation of β-ketoacids.(For structural formula pl see the pdf file)

El objetivo principal que se plantea en el presente trabajo es determinar la plasticidad del crecimiento radial del pino carrasco (Pinus halepensis Mill.) frente al clima. Más concretamente, evaluar el grado de adecuación del crecimiento en grosor del tronco de las masas forestales de esta especie, a las distintas condiciones climáticas que se encuentran dentro de su área de distribución en España. Dicho propósito se aborda mediante el análisis de las series de crecimiento radial y su relación con el clima a distintas escalas temporales y espaciales. Una primera perspectiva se basa en el seguimiento (realizado con resolución casi quincenal) del crecimiento radial del pino carrasco en una localidad situada dentro del Parc Natural del Garraf (Barcelona, Catalunya). La finalidad de este seguimiento es precisar el grado de ajuste de las tasas de crecimiento radial del pino carrasco a la variabilidad climática inter e intraanual. Dicho de otro modo, delimitar los períodos de actividad y reposo del crecimiento en grosor del tronco y definir qué factores climáticos controlan la formación de los anillos de crecimiento. Los objetivos parciales que se plantean son: (i) Establecer el patrón temporal del crecimiento radial (períodos de crecimiento y reposo). (ii) Determinar el grado de ajuste del crecimiento radial de la especie a la variabilidad climática inter e intraanual a lo largo de los 10 años del seguimiento. (iii) Identificar los factores que determinan las tasas de crecimiento en grosor del tronco, sus efectos en las sus características anatómicas del anillo de crecimiento y, la periodicidad con la que dichos anillos se forman. Los resultados derivados de este seguimiento intensivo del crecimiento radial constituirán una base sólida para la interpretación de los resultados obtenidos en el estudio dendroclimático del pino carrasco en España, el cuál se basa en una red de cronologías del grosor de los anillos de crecimiento lo más extensa posible (temporal y espacialmente). Los objetivos en los que se desglosa este segundo propósito son los siguientes: (i) Establecer una red de localidades representativa del área de distribución de la especie, de los bioclimas en los que habita y del tipo de masas forestales que encontramos en España; y describir detalladamente el clima de cada una de ellas, sus peculiaridades y sus tendencias temporales. (ii) Caracterizar ecológicamente los bosques españoles de pino carrasco, mediante dos parámetros: Uno, la descripción de la estructura demográfica de edades y por tamaños y de las características actuales de las masas forestales (densidad, área basal, estructura espacial, etc.); y dos, la reconstrucción de su historia reciente (últimos 100 años) y obtención de su régimen de perturbaciones. (iii) Establecer las relaciones entre el crecimiento (series del grosor de los anillos) y las condiciones climáticas locales, y de su variación a lo largo del este de la Península e Islas Baleares, resaltando el grado de adecuación del crecimiento radial del pino carrasco al clima en las distintas regiones bioclimáticas en las que se halla. (iv) Analizar la variación espacial de los patrones de crecimiento radial de la especie en España y de su relación con el clima a escala regional; y valorar el grado en que dichas variaciones regionales pueden estar relacionadas con fenómenos de circulación atmosférica de escala global (teleconexiones climáticas). (v) Contrastar la estabilidad temporal de las relaciones crecimiento-clima a escala local y regional. La interpretación de los resultados obtenidos proporcionarán una visión global y precisa de la respuesta al cambio climático que pueden tener los bosques españoles de pino carrasco, la especie más importante en el paisaje español de baja altitud, no sólo por el área de territorio que ocupa sino por su importante función ecológica (ej. prevención de la erosión y perdida de suelo y recuperación del entorno natural después de perturbaciones, especialmente incendios).