Innovative Strategies for the Enantioselective Synthesis of Nitrogen-containing Heterocycles by Chiral Brønsted Acid Catalysis & Nickel Catalyzed Decarbonylative Sp2-sp3 Coupling PDF Download
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Author: Hsuan-Hung Liao
Publisher:
ISBN:
Category :
Languages : en
Pages : 169
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Author: Hsuan-Hung Liao
Publisher:
ISBN:
Category :
Languages : en
Pages : 169
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Author: Bryan Joseph Simmons
Publisher:
ISBN:
Category :
Languages : en
Pages : 558
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This dissertation is divided into two main themes concerning transition metal-mediated methodologies and the synthesis of nitrogen-containing heterocycles. The first part of this dissertation focuses on the development of three new reaction pathways utilizing nickel and palladium. The impact of transition metals in the field of synthetic organic chemistry cannot be overstated, with the 2010 Nobel Prize being awarded for the use of palladium cross-coupling in organic synthesis. The second part of this dissertation aims to expand the synthetic toolbox towards the generation of nitrogen-containing heterocycles. With over 100 FDA-approved drugs containing a nitrogen atom, new methodologies toward these scaffolds remain highly sought after. Chapters One, Two, and Three focus on the development of new methodologies utilizing nickel and palladium catalysis. Chapters One and Two describe our efforts towards the functionalization of the amide moiety. Although amides were once thought to be unreactive due to their resonance stabilization, we sought to probe the utility of amides as a functional group handle. Chapter One focuses on the alkylation of amides using nickel and an organozinc source to generate sp2-sp3 C-C bonds. Chapter Two showcases a methodology to convert secondary and tertiary amides to their corresponding amines using a silane reducing agent and nickel catalysis. Chapter Three discusses an academic and industrial collaboration towards the synthesis of tetra-ortho-substituted biaryls using palladium catalysis. These studies culminated in an extensive computational analysis of the reaction mechanism and the synthesis of numerous atropisomeric biaryls. Chapters Four, Five, and Six detail new methodologies towards the generation of nitrogen-containing heterocycles. With the nitrogen atom being prevalent in numerous FDA-approved drugs, facile routes towards their incorporation remain highly valued. Chapter Four illustrates the elusive 3,4-piperidyne's use in a variety of cycloaddition reactions. This study led to the formation of numerous annulated piperidines and exemplifies the utility of our methodology. Chapters Five and Six utilize the interrupted Fischer indolization reaction to produce an assortment of furanoindoline and pyrrolidinoindoline products. Chapter Five centers on the synthesis of the aza-analogues of these products by employing pyridylhydrazines. A computational study was undertaken to determine the cause of success or failure in this transformation. Chapter Six describes a variation of interrupted Fischer indolization methodology performed in a microfluidic device, which should enable its use in medicinal chemistry.
Author: Helene Pellissier
Publisher: Royal Society of Chemistry
ISBN: 1782626700
Category : Science
Languages : en
Pages : 405
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Book Description
Due to the lower costs of nickel catalysts and the high abundance of nickel complexes, enantioselective nickel-mediated transformations have received a continuous and growing attention in recent years. This book demonstrates the diversity of chemistry catalysed by chiral nickel catalysts. Discussing several different enantioselective transformations, this book presents the impressive range of uses that have been found for novel and already known nickel chiral catalysts, from basic organic transformations to completely novel methodologies including fascinating one-pot domino and multicomponent reactions. This much-needed book is ideal for researchers and industrialists in organic chemistry, synthesis and medicinal chemistry.
Author: Adisak Chatupheeraphat
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Author: Dillon Harding Miles
Publisher:
ISBN:
Category :
Languages : en
Pages : 225
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Although the topics discussed in this dissertation each stand as unique areas of research in their respective fields, they are united under the common approach of using catalyst structure to control the selectivity of a particular reaction. For the majority of these transformations, use of a chiral counterion-based catalyst, a relatively new strategy in the field of asymmetric synthesis, proved essential for successful enantioinduction. An additional subtheme, design and application of electrophilic reaction components, provided an added dimension of control to the reaction outcome. Chapter 1 presents a brief perspective on the gold-catalyzed synthesis of heterocycles with an emphasis on previously published hydrofunctionalizations of allene substrates containing tethered nucleophiles, thus providing context for Chapter 2. Chapter 2 describes efforts toward the gold(I)-catalyzed enantioselective bromocyclization of allenes. The primary goal of this project was the synthesis of enantioenriched vinyl halide-containing products containing enantioenriched allylic stereocenters within a heterocyclic ring moiety. Efforts to synthesize these molecules were initially hindered if more traditional electrophilic halogen sources such as N-bromosuccinimide were used; however, employment of the relatively unexplored N-bromolactams resulted in high yields and selectivities of the desired products. Additionally, this methodology partially utilized chiral phosphate-based molecules as counterions as an additional source of chiral information. Chapter 3 takes inspiration from the previous use of chiral phosphate counterions to accomplish an enantioselective intermolecular [alpha]-amination reaction utilizing nucleophilic nitrogen sources. This project sought a reaction complementary to previously existing versions which utilized electrophilic sources of nitrogen. Choice of chiral phosphoric acid in addition to an appropriately activated azoalkene substrate was critical for the high levels of yield and enantioselectivity observed. While expanding the substrate scope, a serendipitous kinetic resolution was observed, which revealed an interesting mode of reactivity associated with [alpha]-arylamino hydrazones. Chapter 4, the final installment, is intended to be an initial survey of explorations into Pummerer-like reactivity again utilizing chiral phosphoric acids or phosphates as a source of chirality. Still in its infancy, this project has explored various carbon-heteroatom bond-forming reactions utilizing either sulfoxide or fluorosulfonium moieties as a source of oxidized sulfur to enable an enantioselective cross-dehydrogenative coupling using a Pummerer-like reaction mechanism. One eventual goal would be to expand the space of enantioenriched sulfur-containing heterocycles.
Author: Gerald B. Rowland
Publisher:
ISBN:
Category :
Languages : en
Pages :
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ABSTRACT: The development of enantioselective reaction methodology has been at the forefront of research in both academic and industrial research laboratories due to the importance of chiral molecules in biological systems. An emerging area of research in the development of enantioselective reaction methodology has been the development of organocatalytic reactions. Organocatalysis, the use of small, chiral organic molecules as catalysts, has the advantage over traditional Lewis acid catalysis in that the reactions in general produce less toxic by-products. One recent breakthrough in the development of enantioselective methodology has been the development of chiral phosphoric acids as organocatalysts. Chiral phosphoric acids have been shown to be excellent catalysts for a wide variety of reactions. In this thesis chiral phosphoric acid-catalyzed enantioselective reaction methodologies have been developed for the addition of sulfonamides and indoles to imines. The development of Bronsted acid-catalyzed amidation of imines allows for an expedient route for the synthesis of N, N-animals, which have been incorporated into a wide variety of biologically active compounds. Initial studies were undertaken to determine the practicality of a Bronsted acid-catalyzed method for the addition of amides to N-Boc protected imines. Over 20 achiral Bronsted acids were screened, and it was found that phenylphosphinic acid and trifluoromethanesulfinimide were both excellent catalysts for the addition of amides to a variety of imines giving the respective products in excellent yield. The methodology was extended to the development of an enantioselective method for the addition of sulfonamides to imines. It was found that a chiral phosphoric acid derived from the VAPOL ligand was suitable for this purpose. The developed methodology is capable of tolerating a wide variety of functional groups allowing for the preparation of the N, N-aminal products in excellent yield and enantioselectivities. An enantioselective phosphoric acid-catalyzed aza-Friedel-Crafts reaction between N-benzylindoles derivatives and N-benzoyl protected imines has been developed. A catalyst derived from the BINOL backbone was found to be the optimum catalyst for the enantioselective transformation. The developed methodology was capable of tolerating a wide variety of functional groups and provides an expedient route for the synthesis of chiral 3-indolylmethanamines.
Author: Angela Marinetti
Publisher: World Scientific
ISBN: 9811248443
Category : Science
Languages : en
Pages : 501
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Book Description
This book illustrates the broad field of enantioselective catalysis by highlighting a few topics, out of myriads, with the double aim to typify selected synthetic achievements and future challenges. Eleven research groups have highlighted topics of interest in either organo- or organometallic catalysis, related to their own expertise. For mature fields, these short chapters, far from being exhaustive, show updated overviews including major recent advances and disclose a few prospects. Other chapters focus on upcoming topics in enantioselective catalysis, i.e. on classes of reactions or families of catalysts that are expected to provide appealing synthetic tools when suitably mastered. For all these areas, recent studies demonstrate highly promising perspectives.
Author: Jose L Vicario
Publisher: Royal Society of Chemistry
ISBN: 1849732183
Category : Science
Languages : en
Pages : 365
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Book Description
This book, unique in its field, is a comprehensive description of all the methodologies reported for carrying out conjugate addition reactions in a stereoselective way, using small chiral organic molecules as catalysts (organocatalysts). In the last 3-4 years, this has been a rapidly growing field in organic chemistry, and many papers have appeared reporting excellent protocols for carrying out these highly efficient transformations that compete well with other classical approaches using transition metal catalysts. A particularly attractive feature of this transformation relies upon the fact that the conjugate addition (Michael and Hetero-Michael reactions) is an extraordinarily effective means to initiate cascade processes which result in the formation of complex molecules from very small and simple starting blocks. The book, written by noted experts, covers all recent advances in this hot topic, and provides a good state-of-the-art review for organic chemists working in this field and all those who wish to start projects in this area.
Author: Uli Kazmaier
Publisher: Springer Science & Business Media
ISBN: 3642227481
Category : Science
Languages : en
Pages : 354
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Book Description
Giovanni Poli, Guillaume Prestat, Frédéric Liron, Claire Kammerer-Pentier: Selectivity in Palladium Catalyzed Allylic Substitution.- Jonatan Kleimark and Per-Ola Norrby: Computational Insights into Palladium-mediated Allylic Substitution Reactions.- Ludovic Milhau, Patrick J. Guiry: Palladium-catalyzed enantioselective allylic substitution.- Wen-Bo Liu, Ji-Bao Xia, Shu-Li You: Iridium-Catalyzed Asymmetric Allylic Substitutions.- Christina Moberg: Molybdenum- and Tungsten-Catalyzed Enantioselective Allylic Substitutions.- Jean-Baptiste Langlois, Alexandre Alexakis: Copper-catalyzed enantioselective allylic substitution.- Jeanne-Marie Begouin, Johannes E. M. N. Klein, Daniel Weickmann, B. Plietker: Allylic Substitutions Catalyzed by Miscellaneous Metals.- Barry M. Trost, Matthew L. Crawley: Enantioselective Allylic Substitutions in Natural Product Synthesis.
Author: Jacob Edward Dander
Publisher:
ISBN:
Category :
Languages : en
Pages : 419
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This dissertation describes efforts in the field of nickel-catalyzed amide C-N bond activations and studies toward the total synthesis of dodecahedrane. Although amide C-N bonds are generally considered inert, recent progress in the activation of these bonds has allowed for their use as synthetic building blocks. Herein, several nickel-catalyzed transformations of amides and strategies to improve the practicality of these reactions are outlined. Each of these studies highlights the utility of nickel catalysis and amides in the context of organic synthesis. Furthermore, a synthetic strategy for and experimental progress toward the synthesis of dodecahedrane are reported. The realization of this total synthesis is expected to push our understanding of molecular reactivity and represent a milestone in the field of total synthesis. Chapters one, two, and three describe the development of transformations and experimental techniques that improve the scope and practicality of nickel-catalyzed activations of aryl amide C-N bonds. More specifically, chapter one describes a nickel-catalyzed alkylation of amides to access aryl-alkyl ketone products. This catalytic methodology represents a mild approach to synthesizing these products that is complementary to the Weinreb ketone synthesis. Chapter two details a strategy for the benchtop delivery of Ni(cod)2. The air- and moisture-sensitivity of this important nickel precatalyst limits its general utility. By utilizing paraffin-Ni(cod)2 capsules, a variety of nickel-catalyzed transformations, including aryl amide cross-couplings, can be performed outside of a glovebox. Chapter three outlines efforts to deploy paraffin-Ni(cod)2 capsules in an undergraduate organic chemistry laboratory. Through the use of these reagents in an esterification of an aryl amide, students gain meaningful insights into frontiers in cross-coupling research, nickel catalysis, and the use of amides in synthetic organic chemistry. Chapters four and five are concerned with the development of nickel-catalyzed transformations of aliphatic amides. Chapter four specifically details efforts to develop a nickel-catalyzed transamidation of aliphatic secondary amides. Through the use of a two-step activation-cross-coupling approach, we have achieved a mild and general solution to this long-standing problem in organic chemistry. Chapter five describes a method for performing arylations of aliphatic amides on the benchtop. By employing paraffin-Ni(cod)2/Benz-ICy[TM]HCl capsules, Suzuki-Miyaura cross-couplings of aliphatic amides to generate aryl-alkyl ketones can be achieved without the need for glovebox manipulations. Both of these studies expand the field of nickel-catalyzed amide C-N bond activations and promote amides as useful synthetic building blocks. Chapter six illustrates a chemoenzymatic approach to enantioselective transformations of amides. The development of a one-pot Suzuki-Miyaura cross-coupling and ketoreductase-mediated reduction allows for rapid, selective access to enantioenriched alcohol products from amides. This methodology represents the first enantioselective transformation of amides that relies on amide C-N bond activation and is expected to guide the development of other asymmetric transformations of amides. Finally, chapter seven details a strategy for the total synthesis of the complex hydrocarbon dodecahedrane. Our proposed symmetry-based approach to this fascinating icosahedral molecule relies on an ambitious [2+2+2+2+2] cyclization to assemble five key C-C bonds in a single synthetic operation. Current efforts to synthesize the necessary substrate for the [2+2+2+2+2] cyclization are detailed. If successful, these studies should provide efficient access to dodecahedrane and are expected to lead to insights into new modes of reactivity.
