京都大学 / 新制・課程博士 / 博士(理学) / 甲第23038号 / 理博第4715号 / 新制||理||1676(附属図書館) / 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 若宮 淳志, 教授 時任 宣博 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

This thesis describes research conducted since September 2006 in Prof. Robert Batey’s laboratory. The thesis is divided into four chapters. Chapter one presents a general introduction of domino reactions, sigmatropic rearrangements, and the allylic azide rearrangement. Several factors affecting the allylic azide rearrangement along with some respective examples are presented. Chapter two describes an efficient synthesis of azido unsaturated ester compounds using a microwave-assisted domino allylic azide / Johnson-Claisen rearrangement. The domino rearrangement reaction proceeds to give the azido ester compounds in good yield and excellent diastereoselectivity. The synthesis of vinyl epoxides and hydroxy allylic azides starting materials are also presented. In addition, other variants of Claisen rearrangements are briefly discussed. Chapter three describes a microwave-assisted domino allylic azide / Overman rearrangement process. The scope of the domino rearrangements, including an example involving an enantioenriched compound, is presented. The product of the domino rearrangements can be used as precursors to 1,2-vicinal diamines. Several functional group transformations and potential application of the product of the domino rearrangement are also described. Chapter four provides the synthesis of cis-2,5-disubstituted pyrrolidines from domino reduction / cyclization of γ-azido-α,β-unsaturated ketones. The overall process involves hydrogenation of the alkene and the azido group, followed by intramolecular cyclization and loss of H2O to form an imine, which is further reduced to give cis-2,5-disubstituted pyrrolidines. The reaction proceeds cleanly to give the products in high yield and with a very high diastereoselectivity ratio. In addition, the formation of pyrrolidinones via domino reduction / cyclication of γ-azido esters are also reported

This thesis describes research conducted since September 2006 in Prof. Robert Batey’s laboratory. The thesis is divided into four chapters. Chapter one presents a general introduction of domino reactions, sigmatropic rearrangements, and the allylic azide rearrangement. Several factors affecting the allylic azide rearrangement along with some respective examples are presented. Chapter two describes an efficient synthesis of azido unsaturated ester compounds using a microwave-assisted domino allylic azide / Johnson-Claisen rearrangement. The domino rearrangement reaction proceeds to give the azido ester compounds in good yield and excellent diastereoselectivity. The synthesis of vinyl epoxides and hydroxy allylic azides starting materials are also presented. In addition, other variants of Claisen rearrangements are briefly discussed. Chapter three describes a microwave-assisted domino allylic azide / Overman rearrangement process. The scope of the domino rearrangements, including an example involving an enantioenriched compound, is presented. The product of the domino rearrangements can be used as precursors to 1,2-vicinal diamines. Several functional group transformations and potential application of the product of the domino rearrangement are also described. Chapter four provides the synthesis of cis-2,5-disubstituted pyrrolidines from domino reduction / cyclization of γ-azido-α,β-unsaturated ketones. The overall process involves hydrogenation of the alkene and the azido group, followed by intramolecular cyclization and loss of H2O to form an imine, which is further reduced to give cis-2,5-disubstituted pyrrolidines. The reaction proceeds cleanly to give the products in high yield and with a very high diastereoselectivity ratio. In addition, the formation of pyrrolidinones via domino reduction / cyclication of γ-azido esters are also reported

Les cyclopropanes sont rencontrés dans de nombreux produits naturels ou synthétiques bioactifs. Les travaux exposés dans ce manuscrit portent sur le développement de réarrangements sigmatropiques [3,3] impliquant des dérivés de cyclopropénylcarbinols pour accéder à des alkylidènecyclopropanes fonctionnalisés, précurseurs de cyclopropanes diversement substitués. Le réarrangement des cyanates de cyclopropénylcarbinyle a permis d'obtenir des dérivés N-acylés d'alkylidène(aminocyclopropanes). Une méthode efficace et stéréosélective, impliquant le réarrangement d'Ireland-Claisen des glycolates et glycinates de cyclopropénylcarbinyle, a également été mise au point pour synthétiser des alkylidènecyclopropanes possédant un motif α-hydroxy ou α-amino acide. Le champ d'application de ce réarrangement a été étendu avec succès à des gem-difluorocyclopropènes. L'hydrogénation diastéréosélective des alkylidènecyclopropanes diversement substitués issus de ces rérrangements sigmatropiques a ensuite permis d'obtenir des cyclopropanes fonctionnalisés. / The cyclopropane ring is ubiquitous in natural and biologically active compounds. [3,3]-Sigmatropic rearrangements of cyclopropenylcarbinol derivatives have been developed to access functionalized alkylidenecyclopropanes, which are useful precursors of diversely substituted cyclopropanes. We have shown that the rearrangement of cyclopropenylcarbinyl cyanates could be accomplished under mild conditions to obtain N-acyl alkylidene(aminocyclopropanes). The Ireland–Claisen rearrangement of glycolates or glycinates derived from secondary cyclopropenylcarbinols has been developed as an efficient and stereoselective method for the synthesis of alkylidenecyclopropanes possessing an α-hydroxy or α-amino acid moiety. The scope of this transformation was successfully extended to gem-difluorocyclopropenes. The alkylidenecyclopropanes resulting from these latter sigmatropic rearrangements are valuable precursors of substituted cyclopropanes by diastereoselective hydrogenation of the exocyclic olefin.

A summary of research conducted since September 2007 at the University of Toronto in the laboratory of Professor Robert A. Batey is presented in this thesis, which is divided into four chapters. The first chapter contains a two-part introduction, where aryl- and aliphatic-Claisen rearrangements are discussed in part 1, and the nucleophilic addition of organoboron reagents to unsaturated C–N functionalities is described in part 2. Chapter 2 contains research involving synthetic and theoretical studies of aryl-Claisen rearrangements and other sigmatropic reactions. The work towards developing the lanthanide-catalyzed domino aryl-Claisen rearrangement for the synthesis of contiguous aryl–C(sp³) moieties is presented first. This is followed by computational studies involving E/Z-selectivity differences for the aryl-Claisen rearrangement, which was an issue noted for the domino aryl-Claisen reaction of a linear substrate. The mechanistic origins of E/Z-selectivity differences for the mono aryl-Claisen rearrangement, which was experimentally ambiguous for over 40 years, is resolved through computational methods. A theoretical analysis of selectivity differences for the allylic azide rearrangement is also described. The third section contains a discussion of Eu(fod)3-catalyzed aryl-Claisen rearrangements on vinyl bromide systems and preliminary studies involving application of the substrates in cross-coupling reactions, and other attempted mono- and domino sigmatropic rearrangements are presented in the fourth section. In chapter 3, the search for computational methods that can accurately predict experimental free energy of activation barriers for the aliphatic-Claisen rearrangement through benchmarking studies with a priori kinetic barrier and kinetic isotope effect data is described. Methods were found to predict new valid transition states and predict ΔG‡ values with a mean unsigned error of 0.3 kcal/mol relative to experimental values. In chapter 4, the development of new allylboration reaction is outlined, involving the double allylboration of nitriles and anhydrides, and initial studies towards the first aminoallylboration reactions of N-aluminoaldimines to form 1,2-diamines.

The [2,3]-sigmatropic rearrangement is a pericyclic reaction of great synthetic utility to organic chemists. Within the scope of this reaction exist some cases in which the product corresponding to a [1,2] rearrangement is formed, despite the fact this is a forbidden process. Generally this is explained by a radical dissociation-recombination pathway; however, studies into the failure of transition state theory and the necessity to incorporate dynamic effects into mechanistic theory lead us to believe such products may arise from these phenomena. In particular, the possibility that many of these products result from an “unsymmetrical bifurcating surface” in the potential energy landscape is intriguing. To investigate this possibility, the Sommelet-Hauser rearrangement of N-allyl-N,N-dimethylglycine methyl ester was explored. The combined use of experimental and theoretically predicted kinetic isotope effects (KIEs) has been previously shown to deliver great mechanistic insight into reactions. The combination of these techniques, however, has found little employ in studying [2,3] rearrangements. This combination was used to study this reaction, using the Singleton method for determining small heavy-atom isotope effects. Resulting experimental KIEs suggest the reaction proceeds by an asynchronous, concerted, early transition state, and is relatively exothermic. This agrees with previous studies and Hammond’s postulate. Predicted theoretical KIEs are in good agreement with experimental KIEs, and the associated transition structure confirms the results suggested by experiment. Interestingly, as calculations proceed from gas phase to solvent models, the activation barrier of the reaction increases, while its exothermicity decreases. The energy difference determined between the lowest and second lowest energy transition structures decreases to 0.81 kcal/mol in the PCM model, so we cannot exclude the contribution of this transition structure to the reaction. However, qualitative results from the associated KIEs and energetics are consistent with the lowest energy transition structure. This reaction does not seem to afford the [1,2] product, and most likely dynamic effects are insignificant in determining product distribution. However, the study has validated, with respect to this body of reactions, both the use of the Singleton method for KIE determination and the combination of these experimental and theoretical techniques.

A summary of research conducted since September 2007 at the University of Toronto in the laboratory of Professor Robert A. Batey is presented in this thesis, which is divided into four chapters. The first chapter contains a two-part introduction, where aryl- and aliphatic-Claisen rearrangements are discussed in part 1, and the nucleophilic addition of organoboron reagents to unsaturated C–N functionalities is described in part 2. Chapter 2 contains research involving synthetic and theoretical studies of aryl-Claisen rearrangements and other sigmatropic reactions. The work towards developing the lanthanide-catalyzed domino aryl-Claisen rearrangement for the synthesis of contiguous aryl–C(sp³) moieties is presented first. This is followed by computational studies involving E/Z-selectivity differences for the aryl-Claisen rearrangement, which was an issue noted for the domino aryl-Claisen reaction of a linear substrate. The mechanistic origins of E/Z-selectivity differences for the mono aryl-Claisen rearrangement, which was experimentally ambiguous for over 40 years, is resolved through computational methods. A theoretical analysis of selectivity differences for the allylic azide rearrangement is also described. The third section contains a discussion of Eu(fod)3-catalyzed aryl-Claisen rearrangements on vinyl bromide systems and preliminary studies involving application of the substrates in cross-coupling reactions, and other attempted mono- and domino sigmatropic rearrangements are presented in the fourth section. In chapter 3, the search for computational methods that can accurately predict experimental free energy of activation barriers for the aliphatic-Claisen rearrangement through benchmarking studies with a priori kinetic barrier and kinetic isotope effect data is described. Methods were found to predict new valid transition states and predict ΔG‡ values with a mean unsigned error of 0.3 kcal/mol relative to experimental values. In chapter 4, the development of new allylboration reaction is outlined, involving the double allylboration of nitriles and anhydrides, and initial studies towards the first aminoallylboration reactions of N-aluminoaldimines to form 1,2-diamines.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

The thesis describes the realization of an asymmetric [2,3]-sigmatropic rearrangement of achiral allylic amines. It is divided into two parts; the first part deals with the development of a Lewis acid-mediated [2,3]-sigmatropic rearrangement and the second the asymmetric version thereof. Quaternization of an -amino amide with various Lewis acids established BBr3 and BF3 to be the most appropriate ones. Various allylic amines were subsequently rearranged into the corresponding homoallylic amines in good to excellent syn-diastereoselectivities, revealing the endo-transition state to be the preferred pathway. The structures of the intermediate Lewis acid-amine complexes were confirmed by NMR spectroscopy studies and DFT calculations. Based on this investigation a chiral diazaborolidine was chosen as Lewis acid and was shown to efficiently promote the asymmetric [2,3]-sigmatropic rearrangement furnishing homoallylic amines in good yields and excellent enantiomeric excesses. In contrast to the achiral rearrangement mediated by BBr3 and BF3, the asymmetric version gave the opposite major diastereomer, revealing a preference for the exo-transition state in the asymmetric rearrangement. To account for the observed selectivities, a kinetic and thermodynamic pathway was presented. On the basis of a deuterium exchange experiment on a rearranged Lewis acid-amine complex and an NMR spectroscopic investigation, the kinetic pathway was shown to be favored. / QC 20100927

In this work, the [3,3] sigmatropic rearrangement of different substituted propargyl thiocyanates and double [3,3] sigmatropic rearrangement of enynyl isothiocyanates either by flash vacuum pyrolysis or by thermolysis in solution are studied. Additionally, the intramolecular reactions of the resulting allenyl isothiocyanates are studied, and the reaction mechanisms for the generation of the final products, such as [1,5] sigmatropic migrations or electrocyclic ring closures, are explained. These highly reactive allenyl isothiocyanates are used as appropriate electrophilic precursors for the preparation of novel examples of thiazoles substituted at C-2 position using different types of nucleophiles. For the formation of these substituted thiazoles, the necessary nucleophilicity as well as the regioselectivity, the stereoselectivity, and the reaction mechanisms are investigated. / In der vorliegenden Arbeit sind die [3,3]-sigmatrope Umlagerung von verschiedenen Propargylthiocyanaten und die doppelte [3,3]-sigmatrope Umlagerung von Eninylisothiocyanaten entweder durch Blitzvakuumthermolyse oder Thermolyse in Lösung untersucht worden. Zusätzlich wurden die intramolekularen Reaktionen der resultierten Allenylisothiocyanate studiert. Außerdem sind die Reaktionsmechanismen zur Bildung der Thermolyseprodukte wie z.B. die [1,5]-sigmatropen Umlagerungen und die elektrocyclischen Ringschlüsse erklärt. Die hochreaktiven Allenylisothiocyanate sind als geeignet elektrophile Vorläufer zur Synthese von neuen Thiazolen verwendbar, die an der C-2 Position substituiert sind. Dabei kommen verschiedene Nucleophile zum Ansatz. Für die Bildung dieser substituierten Thiazole sind die Regioselektivität, Stereoselektivität, Reaktionsmechanismen und der Bereich der einsetzbaren Nucleophile untersucht worden.