京都大学 / 新制・課程博士 / 博士(理学) / 甲第25135号 / 理博第5042号 / 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 Science / Kyoto University / DGAM

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.

Ion-binding organocatalysis is an emerging field that has the potential to control the stereochemical outcome of any transformation that goes via charged intermediates. The aim of this project was to explore how this concept could be applied to an asymmetric allylation reaction. Chapter 2 of this thesis discusses anion-binding catalysis and investigates a chiral cooperative thiourea catalyst that could bind to fluoride to control allylation using an allylsilane. Optimization using a non-chiral thiourea (Schreiner’s catalyst) demonstrated that the reaction proceeded in high yield with TBAT onto an N-benzoylhydrazone. A chiral cooperative thiourea catalyst library was then synthesized but unfortunately, although the allylation using these catalysts proceeded in excellent yield, the product was isolated as the racemate (Scheme 1). Scheme 1: Anion-binding catalysis gave allylated products in high yields but gave no stereocontrol. Chapter 3 examines a chiral quaternary ammonium fluoride as an example of chiral cation-directed catalysis. We hypothesized that an allylsilane activated by fluoride would generate an allyl anion species that would associate with the chiral quaternary ammonium cation through electrostatic interactions. Extensive optimization found that the allylation reaction proceeded in good yield in chloroform at reflux with N-benzoylhydrazones. Different fluoride catalysts were prepared using an ion-exchange resin, and cinchonidine-derived catalysts performed the best. This methodology was extended to a phase-transfer catalyzed process, where solid cesium fluoride exchanged with chloride in situ, removing the need to synthesize and isolate ammonium fluoride catalysts (Scheme 2). Scheme 2: Cation-directed asymmetric allylation. In Chapter 4 cation-directed asymmetric catalysis was extended to an intramolecular allylation reaction. Substrate synthesis was attempted by cross metathesis but the reaction was capricious and yields were low. Intramolecular allylation with these materials gave promising results (Scheme 3) but a lack of material prevented optimization. Scheme 3: Intramolecular allylation results.

The class of polycyclic hydrocarbons including adamantane, pentacyclo [5.4.0.02 ,6. 03,I0.05,9]undecane (PCU) and trishomocubane have proven to be an exciting investigation for synthetic chemists. Many derivatives have been shown to possess excellent antiviral and antibacterial properties, as well as potent anti-Parkinson agents. Some improve the lipophilic nature of biologically active drugs, while others affect the three-dimensional structure of peptides once incorporated as amino acid analogues. This investigation focussed on deriving routes to improve yields of racemic 4-amino-(D3)trishomocubane- 4-carboxylic acid (tris-amino acid), the synthesis of enantiomerically pure tris-amino acid, the incorporation of tris-amino acid into a short peptide, as well as the simulation of the rearrangement of PCU to trishomocubane by using computational tools. Research into developing a more efficient hydrolysis of trishomocubane-hydantoin (trishydantoin) to yield racemic tris-amino acid, led to the development of two novel compounds: the mono-Boc [Novel Compound 1, (NC1)] and bis-Boc [Novel Compound 2, (NC2)] protected hydantoin. Base hydrolysis of NC2 quantitatively yielded the racemic tris-amino acid, which was a significant improvement on previously documented synthetic routes. The first attempt to produce enantiomerically pure tris-amino acid was through the synthesis of diastereomeric derivatives of tris-hydantoin, chromatographic separation of the diastereomers, followed by base hydrolysis of the hydantoin ring to produce enantiomerically pure tris-amino acid. This research led to the development of two novel N-protected tris-hydantoin derivatives (NC3 and NC4). Failure to chromatographically separate the diastereomers resulted in the abandonment of this particular route. The use of enzymes was, therefore, attempted to produce enantiomerically pure tris-amino acid. A novel ester derivative of tris-amino acid (NC5) was synthesised, which was followed by the application of Pig Liver Esterase (PLE). PLE is an enzyme which cleaves ester functionalities. Some success was achieved but the extremely low yields of enantiomerically pure tris-amino acid did not warrant this enzyme as a viable route for production of the desired product. Solid phase techniques were employed for the production of a tripeptide consisting of alanine-glycine-tris-amino acid (ala-gly-tris). Some difficulty was encountered in extending the amino acid sequence due to suspected Schiff base interaction between the free amino group of tris-amino acid and the carbonyl functionality of glycine in the second position. A computational study, using ab initio methods, was performed on the rearrangement of the PCU diol to 7-fluoro-11-hydroxy-trishomocubane. Two mechanisms (Proposed Mechanism 1 and Proposed Mechanism 2) were explored and both showed that the stereochemistry of the hydroxyl groups has only a marginal influence on the transition state energies of the various isomers. Both mechanisms were also indicated to occur through an intramolecular SN2 mechanism. / Thesis (M.Sc.)-University of Natal, Durban, 2003.

Introduction: The introduction provides a survey of the natural product and pharmaceutical targets accessible from dihydropyridines and dihydropyridones as well as an overview of previous work carried out towards the synthesis of these valuable intermediates. The mechanism, scope and limitations of the various approaches are covered, along with the goals of this project. Results and Discussion: A Regioselective Route to Dihydropyridones. The regioselective addition of nucleophiles to a range of disubstituted pyridinium salts has been achieved, with selectivity determined by hard/soft factors. Certain nucleophiles can be added with complete regioselectivity to either C-2 or C-6 of these salts, depending on the conditions employed. Addition at C-2 allows the generation of a quaternary centre in high yield. The conditions discovered can be applied to pyridinium salts with different substitution patterns and an effective procedure has been developed for the removal of the nitrogen protecting group post reduction. The Preparation of Enantiopure Dihydropyridones.After unsuccessful attempts to find a reagent-controlled asymmetric synthesis of dihydropyridones, a highly diastereoselective and non-chiral auxiliary based substrate-controlled procedure has been developed. By prompting an intramolecular hydride migration from a secondary silyl ether onto the pyridinium core, the corresponding dihydropyridones are available in high yield, with the diastereoselectivity being controlled by the minimization of 1,3-allylic strain between the N-allyl group and the hydride-bearing side chain. Thus, an enantiopure pyridyl alcohol may be converted to the corresponding dihydropyridone without loss of enantiomeric purity. Furthermore, the dihydropyridones can be easily converted to complex bicyclic systems via a ring closing metathesis reaction. Experimental: Full experimental procedures and spectroscopic characterization of compounds are provided.

This thesis is concerned with the asymmetric conjugate addition reactions of a range of chiral nucloeophiles. Chapter 1 introduces the conjugate addition reaction as a valuable carbon-carbon and carbon-heteroatom bond forming reaction in organic chemistry, and explores the asymmet- ric conjugate addition of a range of chiral and achiral carbon and nitrogen nucleophiles to a range of acceptors. Chapter 2 explores the use of the N-benzyl-N-(α-methylbenzyl)amino group as a chi- ral auxiliary, by employing the attempted conjugate additions of both N-benzyl-N-(α- methylbenzyl)hydrazine and N -benzyl-N -(α-methylbenzyl)hydroxylamine as chiral ammo- nia and water equivalents respectively. Chapter 3 describes the asymmetric and stereoselective preparation of a range of 4,4- disubstituted isoxazolidin-5-ones from the conjugate addition of lithium (S)-N-tert-butyl- dimethylsilyloxy-N -(α-methylbenzyl)amide. The isoxazolidin-5-ones are then globally de- protected via hydrogenolysis, giving rise to the corresponding β^2,2,3-amino acids. Chapter 4 focuses on the development of a protocol to effect the conjugate addition of a chiral aniline equivalent. The scope of the reaction is delineated by varying both the nu- cleophile and the α,β-unsaturated ester. Finally, cyclisation of the β-N-arylamino esters to the corresponding tetrahydroquinolines is explored, and an application to the synthesis of the natural product (−)-angustureine is presented. Chapter 5 contains full experimental procedures and characterisation data for all com- pounds synthesised in Chapters 2, 3 and 4.

Direct generation of enantioenriched mono-α-alkylated aldehydes by intermolecular nucleophilic substitution is a general and long-standing problem in synthesis, and is of importance due to the diverse reactions such aldehydes undergo for introducing asymmetry into molecules. The work described in this thesis initially details the development of the first lithium amide capable of efficiently converting terminal epoxide into enamine functionality, where the latter also demonstrates effective C-alkylation activity. Not only addition to Michael acceptors, but more notably substitution using activated organohalides (α-bromoacetates, benzyl, allyl and propargyl bromide) gave the corresponding α-substituted aldehydes in good to excellent yields. Alkylation with propargyl bromide yielded only the propargyl-substituted aldehyde with none of the corresponding allene observed; this result shows that N-alkylation followed by [3,3] sigmatropic rearrangement is not occuring. Importantly, a range of short-, longer-chain and secondary unactivated alkyl iodides also proved viable. Significantly, with chiral lithium amides, the corresponding chiral enamines could be alkylated with strongly electrophilic benzyl, allyl and propargyl (no allene seen) bromides in very good yields, and with short chain alkyl iodides – MeI and EtI in satisfactory yields, to provide the first direct access to α-alkylated aldehydes with high asymmetric induction by intermolecular nucleophilic substitution.

Since 2000 the organocatalytic synthesis has developed massively in a third pillar of asymmetric synthesis standing next to catalysis with metal complexes and enzymatic catalysis. Organocatalysts, due to their various activation modes which could be combined in domino reactions, offer a way for a synthesis of complex molecules from a simple starting material. This thesis deals with investigation of usage of chiral secondary amines as catalysts for asymmetric synthesis of cyclic compounds. The main part of research was devoted to development of organocatalytic method leading to synthesis of enantiomerically pure cyclopentanecarbaldehydes and nitrocyclopentanecarbaldehydes. We focused also on the organocatalytic preparation of cyclohexanecarbaldehydes. During this work we developed an asymmetric domino Michael addition/α- substitution reaction of 2-(2-bromoethyl)malonates resp. 1-bromo-3-nitropropane with various enals catalyzed by chiral secondary amine. In the first case cyclopentanecarbaldehydes were formed where two chiral centres were created. In second case nitrocyclopentanecarbaldehydes were formed where three chiral centres were created. Yields of such developed reaction protocol reach up to 74 % and the reaction proceeds with excellent diastereo- and enantioselectivity (up to 19:1 d.r. and...

Development of new asymmetric processes is one of the objectives of catalysis in organic chemistry. These processes can provide access to chiral building blocks applicable in syntheses of various natural substances that can be used for medical purposes. One such process is the preparation of chiral homoallyl alcohols, which have been used for syntheses of variety of biologically active compounds. In view of the aforementioned, suitably substituted homoallyl alcohols could be used as intermediates in syntheses of koibacins A-D, which have a number of interesting biological properties. Natural koibacins A-D are metabolites isolated from the marine cyanobacterium Oscillatoria sp. that exhibits selective antileishmanial activity and potent antïinflammantory properties. Our synthetic plan is focused on an approach through the allylation of aldehydes, esterification, ring closing metathesis and finally cross metathesis with different lipophilic fragments. Key words: enantioselective allylation, asymmetric synthesis, natural compounds, coibacins.

Les 2,2´-bipyridines et leurs homologues, les N,N´-dioxydes, appartiennent à une classe de composés hétéroaromatiques très importante ayant montré de nombreuses applications dans le domaine de la chimie et principalement en synthèse asymétrique. Une des méthodes les plus performantes pour leurs synthèses s´est révélée être une réaction de cocyclotrimérisation d´alcynes en présence de dérivés nitriles.Une nouvelle variante de la réaction de cyclotrimérisation – cocyclotrimérisation de diynes halogénés avec des dérivés nitriles – permettant la formation de composés 2- et3-halogéno-pyridines a ainsi été développée. La réaction a été étudiée sur une large gamme de substrats permettant l´accès à une librairie de pyridines avec de bons rendements. La formation d´un sous-produit, issu d´un échange d´halogène, a été approfondie au cours de l´étude et son origine a été élucidée grâce à différentes expériences.Les 2-halogéno-pyridines ont été utilisées comme réactifs de départ pour la synthèse de ligands chiraux de type 2,2´-bipyridines. L´étape problématique s´est avérée être la réaction de dimérisation réductrice des 2-halogéno-pyridines donnant accès aux2,2-bipyridines correspondantes. L´efficacité de ces ligands chiraux de type 2,2´-bipyridinea été évaluée dans différentes réactions asymétriques catalysées par des métaux de transition telles que l´aldolisation de Mukaiyama, l´hydroxyméthylation, l´addition conjuguée, l´activation C–H d´indoles mais aussi la désymmétrisation d´époxydes meso, dans laquelle un des ligands bipyridines a montré une extraordinaire activité et robustesse. Ensuite, basées sur des analyses RMN, des calculs DFT et des analyses par diffraction des rayons X, les propriétés structurales de ce ligand ont été étudiées.De plus, une nouvelle famille de catalyseurs à chiralité axiale de type 2,2´-bipyridines N,N´-dioxydes a pu être synthétisée via 2 différentes approches, où seule l´étape clé de dimérisation diffère. La première approche, basée sur la réaction de dimérisation réductrice des 2-halogéno-pyridines, permet l´obtention d´un seul atropoisomère du N,N´-dioxydes cible après une séquence réactionnelle de 8 étapes tandis que la seconde approche, basée sur la réaction de dimérisation oxydante de pyridines N-oxydes, donne l´accès aux 2 atropoisomères en seulement 5 étapes. Le champs d´application de ces nouveaux catalyseurs de typeN,N´-dioxydes, en tant que base de Lewis, a été examiné dans l´allylation énantiosélective du benzaldéhyde ainsi que dans l´aldolisation de l´acétal de cétène trichlorosilylé en présence de l´acétophénone. / 2,2'-Bipyridines and their appropriate N,N'-dioxides form a significant class of heteroaromatic compounds, which has found application in various fields of chemistry and predominantly in asymmetric catalysis. One of the most powerful methods for their synthesis is cocyclotrimerization of alkynes with nitriles.A new variant of cyclotrimerization reaction – cocyclotrimerization of halodiynes with nitriles, which results in the formation of 2- and 3-halopyridines, has been developed. The reaction was studied on a wide range of substrates providing the pyridine products in good isolated yields. Formation of an unexpected product of halogen exchange reaction was observed during the course of the study and its origin was elucidated by experimental studies.The prepared 2-halopyridines were used as starting materials for syntheses of new chiral 2,2'-bipyridine ligands. The crucial step of their synthesis turned out to be the reductive dimerization of 2-halopyridines to the corresponding 2,2'-bipyridines. Application of the formed bipyridine ligands was then tested in various metal-catalyzed asymmetric reactions, namely Mukaiyama aldol reaction, hydroxymethylation, conjugate addition, C–H activation of indole and desymmetrization of meso-epoxides, in which one of the bipyridine ligands showed extraordinary activity and robustness. The structural properties of this ligand were then studied based on the NMR analyses, DFT calculations and single crystal X-ray analyses.New axially chiral 2,2'-bipyridine N,N'-dioxides were synthesized via two approaches, which differed in the type of the key dimerization step. While the first approach, based on the reductive dimerization of 2-halopyridines, furnished only one atropoisomer of the target N,N'-dioxide by an eight-step reaction sequence, the second approach, based on oxidative dimerization of pyridine-N-oxides, provided both atropoisomers in only five steps. The applicability of these novel N,N'-dioxides as Lewis base catalysts were then examined in the enantioselective allylation of benzaldehyde and aldol reaction of trichlorosilyl ketene acetal with acetophenone.