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The formation of saturated carbon-carbon bonds in a precise and controlled manner is arguably the principal objective of organic synthesis. Carbocyclic ring systems comprise the underlying structure for the preponderance of natural products and pharmaceutical agents. Therefore, synthetic methods capable of selectively initiating polycyclization processes in the presence of spectating functionality are of significant value, particularly so when multiple stereocenters are formed enantioselectively. The emergence of phosphine gold(I) catalysis over the past decade has opened up new avenues to carbocycle formation via pi activation of alkynes occurring under exceedingly mild conditions and with excellent chemoselectivity. The research described herein describes the use of homogenous gold(I) complexes to initiate electrophilic cyclization cascades. Through rational substrate design, carbocationic centers may be generated in a predictable manner and employed in subsequent intramolecular cyclization processes. Chapter 1 introduces the unique reactivity observed in complexes of gold imparted by its relativistically accelerated valence electrons. One consequence of this perturbation is the linear geometry maintained by gold(I) complexes, minimizing the influence of ligand-based chirality on reactions occurring at coordinated alkynes. In spite of this challenge, moderate levels of enantioselectivity were achieved in the desymmetrization of dienynes by cycloisomerization using chiral bisphosphite gold(I) catalysts. Ultimately, we were able to achieve selectivities up to 98% ee using hindered chiral bisphosphine gold(I) catalysts during the evaluation of another enyne cycloisomerization reaction, described in chapter 2. In this process, an initial regioselective cyclization was used to generate a carbocationic species poised to undergo intramolecular trapping. Consistently high enantioselectivity was maintained using various pendant oxygen, carbon and nitrogen nucleophiles. The diastereomerically pure bi- and tricyclization products obtained provided support for a concerted polyene cyclization mechanism as predicted by the Stork- Eschenmoser postulate. Chapter 3 describes another tandem process exploiting the transient cationic species arising from gold(I)-promoted enyne cycloisomerization. In this case, a gold(I)-initiated tandem cyclopentannulation reaction was employed in the total synthesis of the novel triquinane ventricosene. A cyclopropanol unit embedded in the enyne substrate underwent a semipinacol rearrangement in response to the carbocation, leading cleanly to bicyclo[3.2.0]heptan-6-one products. For cyclopentenyl substrates, the hindered all-carbon quaternary center and all of the ring fusions of the angular triquinane ring system were formed at once. The choice of a hydrocarbon target highlighted the utility of gold(I) catalysts as selective activators of carbon unsaturation; throughout the synthesis only a single heteroatom was present. This work concludes by extending the scope gold(I)-catalyzed carbocyclization reactions which generate useful cationic intermediates. The gold(I)-catalyzed Rautenstrauch rearrangement forms a cyclopentene-based cationic species which was shown to undergo efficient trapping by pendant arenes to give a saturated 5,6-ring fusion comprising a chiral benzylic quaternary center. The chirality transfer observed in the parent process was found to be conserved in the tandem process. Interestingly, cyclization of racemic substrates by chiral bisphosphine digold catalysts was found to proceed with moderate enantioselectivity, suggesting a competing mechanism is in effect which proceeds through an achiral intermediate.
Demonstrates the advantages of catalytic cascade reactions for synthesizing natural products and pharmaceuticals Riding the wave of green chemistry, catalytic cascade reactions have become one of the most active research areas in organic synthesis. During a cascade reaction, just one reaction solvent, one workup procedure, and one purification step are needed, thus significantly increasing synthetic efficiency. Featuring contributions from an international team of pioneers in the field, Catalytic Cascade Reactions demonstrates the versatility and application of these reactions for synthesizing valuable compounds. The book examines both organocatalysis and transition-metal catalysis reactions, bringing readers up to date with the latest discoveries and activities in all major areas of catalytic cascade reaction research. Catalytic Cascade Reactions begins with three chapters dedicated to organocatalytic cascade reactions, exploring amines, Brønsted acids, and the application of organocatalytic cascade reactions in natural product synthesis and drug discovery. Next, the book covers: Gold-catalyzed cascade reactions Cascade reactions catalyzed by ruthenium, iron, iridium, rhodium, and copper Palladium-catalyzed cascade reactions of alkenes, alkynes, and allenes Application of transition-metal catalyzed cascade reactions in natural product synthesis and drug discovery Engineering mono- and multifunctional nanocatalysts for cascade reactions Multiple-catalyst-promoted cascade reactions All chapters are thoroughly referenced, providing quick access to important original research findings and reviews so that readers can explore individual topics in greater depth. Drawing together and analyzing published findings scattered across the literature, this book provides a single source that encapsulates our current understanding of catalytic cascade processes. Moreover, it sets the stage for the development of new catalytic cascade reactions and their applications.
Ana Escribano Cuesta's thesis presents a detailed study of the inter- and intramolecular reactions of carbonyl compounds with 1,6-enynes using gold (I) complexes. An important part of the work involved streamlining the variables that allow the selective synthesis of different products such as tricyclic compounds, dihydropyrans, 1,3-dienes or cyclobutenes. The second chapter highlights the importance and difficulties in synthesising a cyclobutene subunit and the author includes a detailed description of how the products were prepared. The final chapter outlines the synthesis of lundurines using methodology developed by the author's research group for intramolecular gold-catalyzed cyclization of indoles with alkynes. The lundurine products developed in this work show significant in vitro cytoxicity toward B16 melanoma cells. The work in this thesis has led to a number of publications in high-profile chemistry journals.
This book explores efficient syntheses of indole alkaloids based on gold-catalyzed cascade cyclizations, presenting two strategies for total synthesis of these natural products based on gold-catalyzed reactions of conjugated diyne or ynamide. The book first describes the total and formal synthesis of dictyodendrins A–F based on direct construction of the pyrrolo[2,3-c]carbazole core using the gold-catalyzed annulation of azido-diynes and protected pyrrole. This synthetic strategy features late-stage functionalization of the pyrrolo[2,3-c]carbazole scaffold at several positions and allows diverse access to dictyodendrins and their derivatives. Secondly, the book discusses the formal synthesis of vindorosine based on the pyrrolo[2,3-d]carbazole construction using the gold-catalyzed cascade cyclization of ynamide. Importantly, the reaction using a chiral gold complex provides the optically active pyrrolo[2,3-d]carbazole. This strategy facilitates the rapid construction of the pyrrolocarbazole core structure of aspidosperma and related alkaloids, including vindorosine. These methodologies can accelerate the medicinal application of pyrrolocarbazole-type alkaloids and related compounds.
This book explores the possible development of neurokinin-3 receptor (NK3R) antagonists with reduced environmental impact. Pharmaceuticals are used to cure diseases and to alleviate symptoms in humans and animals. However, the stable, bioactive substances excreted by patients have unfavorable effects on non-target species. To overcome these disadvantages of these highly stable, potent substances, drug design to turn off bioactivity after release into the environment is needed. The book describes the development of eco-friendly NK3R antagonists by introducing a labile functional moiety and substituting a scaffold. This resulted in a novel NK3R antagonist that oxidized into its inactive form when exposed to air. Further, the book presents an efficient and easily achievable synthetic method of creating triazolopiperazine scaffolds, as well as a structure–activity relationship study involving scaffold hopping for decomposable motifs, which led to a novel photodegradable NK3R antagonist. Demonstrating that it is possible to develop compounds that convert into their inactive forms under environmental conditions, this book is useful for anyone interested in therapeutic agents with reduced environmental impact.
Significant advances in metal-catalyzed reactions, especially cyclizations, have dramatically improved the efficiency of organic synthesis over the last three decades. To date these transformations are widely used in the area of synthesis of both natural products and therapeutic agents. "Science of Synthesis: Metal-Catalyzed Cyclization Reactions" presents the most commonly used and significant metal-catalyzed reactions for modern organic synthesis. The basic principles, the current state of the art, scope, limitations, and mechanism of these reactions are also discussed. Typical examples of target synthesis are provided to help inspire further applications. Volume 1 covers intramolecular coupling reactions (including Heck reactions), intramolecular allylations, and cyclopropane and cyclopropene ring openings. Also included are cyclization reactions of alkenes, alkynes, and allenes, cycloisomerizations, and intramolecular C-N and C-O bond formation.
Antoine Simonneau's thesis highlights the development of new cycloisomerization reactions through the activation of alkynes with gold complexes. First Simonneau describes 1,6-enynes and their direct conversion into allenes through 1,5-hydride or ester migration processes. The author and his team used appropriate propargylic functional groups to achieve this conversion. This study shows that O-tethered 1,6-enynes carrying a strained cycloalkane at the propargylic position could undergo a cyclopropanation/ring expansion cascade reaction. The author employed this rearrangement as the starting point in the design of a new macro cycle synthesis. The next part of the thesis focuses on the cycloisomerization of diynes involving as the first step of the process the rearrangement of one alkyne partner into an allene thanks to a gold-catalyzed 1,3-shift of a propargylic ester. The thesis discloses a new cycloisomerization pattern featuring a 1,5-carbonyl transfer, giving rise to unprecedented cross-conjugated diketones. In the final part of the research, Simmoneau investigates the gold-catalyzed cycloisomerization mechanism of 1,6-enynes and questions the intermediacy of gold acetylides. By the means of NMR and mass spectrometry analysis, theoretical treatment and solution experiments, it was possible to rule out the involvement of these species in the catalytic cycle. This thesis has led to a number of publications in high-impact journals.
Ynamides contain a triple bond directly connected to a nitrogen atom that bears an electron-withdrawing group. They represent an especially useful and emerging class of reagents, notably because of their strongly polarized triple bond, which enables the development of unique chemical transformations. While they were discovered by Viehe in 1972, their chemistry has remained little investigated and the renaissance of ynamide chemistry started at the dawn of the 20th century with the development of efficient methods for their synthesis. Since then, ynamide chemistry has developed at a remarkably high rate, notably in the past 20 years. Although there are several reviews on ynamide chemistry, most of them are out of date or only focus on special aspects of ynamide chemistry and there is no book about ynamide chemistry yet. Thus, a comprehensive book on ynamide chemistry would be timely and is highly needed. This book covers all aspects of ynamide chemistry, including their discovery, their syntheses, their application in heterocyclic chemistry, natural product synthesis, and organometallic chemistry, and their use as coupling reagents. It provides a systematic and comprehensive overview on ynamide chemistry for the researchers in this field, general readers interested in synthesis, and those who want to enter this field and need a comprehensive and up-to-date overview. Undoubtedly, this book will play a key role in connecting the past with the future to further foster the development of ynamide chemistry.
Reflecting the tremendous growth of this hot topic in recent years, this book covers C-H activation with a focus on heterocycle synthesis. As such, the text provides general mechanistic aspects and gives a comprehensive overview of catalytic reactions in the presence of palladium, rhodium, ruthenium, copper, iron, cobalt, and iridium. The chapters are organized according to the transition metal used and sub-divided by type of heterocycle formed to enable quick access to the synthetic route needed. Chapters on carbonylative synthesis of heterocycles and the application of C-H activation methodology to the synthesis of natural products are also included. Written by an outstanding team of authors, this is a valuable reference for researchers in academia and industry working in the field of organic synthesis, catalysis, natural product synthesis, pharmaceutical chemistry, and crop protection.
The focus of my dissertation work is to study the gold-catalyzed intramolecular and intermolecular cyclizations involving oxonium intermediates towards the application of synthetically interesting frameworks under ambient conditions and developing a rational approach for the effective catalyst design in gold catalysis. We explored the goldcatalyzed oxygen-transfer reactions of 2-alkynyl-1,5-diketones or 2-alkynyl-5-ketoesters to furnish five-membered rings bearing a quaternary carbon tethered to a carbonyl group. The detailed mechanistic investigation on the newly proposed intramolecular [4+2] cycloaddition mechanism was performed by means of isotopic experiments and quantum chemical calculations. The reactivity of alkynylenolate was investigated in the reactions of allenic ketones and vinyl ketones which led to versatile syntheses of 2-alkynyl-1,5-diketones, 4-alkynyl-3-hydroxycyclohexones and 4-alkynylcyclohexenones. We also investigated the gold-catalyzed annulations of 2-alkynyl benzaldehyde with acyclic or cyclic vinyl ethers under very mild conditions, and successfully developed synthetically interesting dihydronaphthalenes, acetal-tethered isochromenes and bicyclo[2.2.2]octane derivatives often found in biologically active molecules and natural products. Although there have been numerous reviews and publications on new gold-catalyzed transformations, the development of new catalysts still relies on a hit-and-miss approach. Because the decay of the active cationic gold catalyst is the main reason for the high catalytic loading required for the majority of gold-catalyzed transformations, we developed a modular approach for effective catalyst design in gold catalysis. We discovered a new phosphine-based precatalyst that is broadly applicable and highly efficient - in the parts per million (ppm) range - at room temperature or slightly elevated temperatures (