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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 (
The ability of gold(I) to activate many types of unsaturated bonds toward nucleophilic attack was not widely recognized until the early 2000s. One major challenge in gold catalysis is the control over regioselectivity when there are two or more possible products as a result of complicated mechanistic pathways. It is well know that the choice of ligand can have dramatic effects on which pathway is being followed but very rarely are the reasons for this selectivity understood. The synthesis of new acyclic diaminocarbenes was developed and a study of the ligand effects on the regioselectivity of a gold-catalyzed domino enyne cyclization hydroarylation reaction and a Nazarov cyclization was undertaken. New chiral acyclic diaminocarbenes were also developed and tested along side new C3-symmetric phosphite ligands in an asymmetric intramolecular hydroamination of allenes. Structure activity correlations were developed for the potential use in further rational ligand design. The synthesis of 6a,7-dihydro-5-amino-dibenzo[c,g]chromene derivatives via a gold-catalyzed domino reaction of alkynylbenzaldehydes in the presence of secondary amines was developed. These were sent to be screened for biological activity.
Research on designing new catalytic systems has been one of the most important fields in modern organic chemistry. One reason for this is the predominant contribution of catalysis to the concepts of atom economy and green chemistry in the 21st century. Gold, considered catalytically inactive for a long time, is now a fascinating partner of modern chemistry, as scientists such as Bond, Teles, Haruta, Hutchings, Ito and Hayashi opened new perspectives for the whole synthetic chemist community. This book presents the major advances in homogeneous catalysis, emphasizing the methodologies that create carbon-carbon and carbon-heteroatom bonds, the applications that create diversity and synthesize natural products, and the recent advances and challenges in asymmetric catalysis and computational research.It provides readers with in-depth information about homogeneous gold-catalyzed reactions and presents several explanations for the scientific design of a catalyst. Readers will be able to understand the entire gold area and find solutions to problems in catalysis.Gold Catalysis — An Homogeneous Approach is part of the Catalytic Science Series and features prominent authors who are experts in their respective fields.
The series Topics in Current Chemistry presents critical reviews of the present and future trends in modern chemical research. The scope of coverage is all areas of chemical science including the interfaces with related disciplines such as biology, medicine and materials science. The goal of each thematic volume is to give the non-specialist reader, whether in academia or industry, a comprehensive insight into an area where new research is emerging which is of interest to a larger scientific audience. Each review within the volume critically surveys one aspect of that topic and places it within the context of the volume as a whole. The most significant developments of the last 5 to 10 years are presented using selected examples to illustrate the principles discussed. The coverage is not intended to be an exhaustive summary of the field or include large quantities of data, but should rather be conceptual, concentrating on the methodological thinking that will allow the non-specialist reader to understand the information presented. Contributions also offer an outlook on potential future developments in the field. Review articles for the individual volumes are invited by the volume editors. Readership: research chemists at universities or in industry, graduate students.
With its impressive features, gold has led to completely new reaction types in recent years, which in turn have strongly influenced both organic catalysis and material science. Other fields where a significant amount of new results has been obtained include nanotechnology, self assembly/supramolecular systems and biochemical/medicinal chemistry. As a result, gold is one of the hottest topics in catalysis at the moment, with an increasing amount of research being carried out in this field. While focusing on homogeneous catalysis, this monograph also covers the main applications in heterogeneous catalysis. Following a look at the gold-catalyzed addition of heteroatom nucleophiles to alkynes, it goes on to discuss gold-catalyzed additions to allenes and alkenes, gold-catalyzed benzannulations, cycloisomerization and rearrangement reactions, as well as oxidation and reduction reactions. The whole is finished off with a section on gold-catalyzed aldol and related reactions and the application of gold-catalyzed reactions to natural product synthesis. Of interest to synthetic chemists and inorganic chemists, as well as organic chemists working in homogeneous catalysis, physical and technical chemists.
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.
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.
Research on designing new catalytic systems has been one of the most important fields in modern organic chemistry, and one reason for this is the predominant contribution of catalysis to the concepts of atom economy and green chemistry in the 21st century. Gold, considered catalytically inactive for a long time, is now a fascinating partner of modern chemistry, as scientists such as Bond, Haruta, Hutchings, Ito and Hayashi opened new perspectives for the whole synthetic chemist community. This book presents the major advances in homogeneous catalysis, emphasizing the methodologies that create carbon-carbon and carbon-heteroatom bonds, the applications that create diversity and synthesize natural products, and the recent advances and challenges in asymmetric catalysis and computational research. The Handbook of Homogeneous Gold Catalysis provides readers with in-depth information about gold-catalyzed reactions and presents several explanations for the scientific design of a catalyst. Readers will be able to understand the entire gold area and find solutions to problems in catalysis. Featuring prominent authors, who are experts in their respective fields, this is the first book dedicated to homogeneous gold chemistry. Contents: From Gold in Nature to Gold Catalysts (S Kramer and F Gagosz); Oxidation and Reduction Reactions (L Zhang); Gold-Catalyzed Addition of Carbon Nucleophile to C-C Multiple Bond (B Simmons and H C Shen); Gold-Catalyzed Addition of Heteroatom Nucleophile to C-C Multiple Bond (N Asao, N Hatakeyama and Y Yamamoto); Gold-Catalyzed Synthesis of Heterocycles (A Arcadi); Multi-Component Reactions (R Skouta and C J Li); Gold Catalyzed Tandem and Cascade Reactions (R-S Liu); Cycloisomerization Reactions of 1, n -Enynes (N Huguet and A Echavarren); Gold-Catalyzed Reaction of Propargylic Esters (L Fensterbank, J-P Goddard, M Malacria and S Simonneau); Gold-Catalyzed Cross-Coupling Reactions (S Blum); Gold-Catalyzed Reactions: A Computational Approach (E Soriano & J Marco-Contelles); Asymmetric Gold-Catalyzed Reactions (P Y Toullec, A Pradal and V Michelet); Gold Catalysis in Natural Product Synthesis (M Gesinski and F D Toste). Readership: Student, professionals.
In the past dozen years, great progress has been made in developing highly efficient homogenous gold catalysis. As soft "pi" Lewis acids, cationic gold(I) complexes are particularly powerful in terms of activating alkyne/allene towards nucleophilic attack, leading to a variety of synthetically versatile structures. During my research, several synthetic methods have been developed, including: (1) Au-catalyzed ligand-directed anti nucleophilic attack of alkynes; the new ligands I developed enable highly efficient gold-catalyzed nucleophilic addition of acids, anilines and water to the alkynes; and catalyst loadings could be lowered to 10 parts per million; (2) rapid access of chroman-3-ones via gold-catalyzed oxidation of propargyl aryl ethers; this step-economic and efficient transformation was realized by a bulky gold catalyst, Me4tBuXPhosAuNTf2 and bulky electron-deficient pyridine N-oxides derived from Hantzsch esters; (3) Au-catalyzed novel indole synthesis via a key [3,3] sigmatropic rearrangement; 2-alkylindoles were produced with high regioselectivity and efficiency from easily accessed N-arylhydroxylamines under mild conditions; an improved approach involved cooperative dual catalysis of Zn and Au was developed; much broader substrate scope, shorter reaction time and good to excellent yields were achieved.
The present work is an organometallic study concerning the chemistry of gold(I) complexes and their reactivity. Of particular interest was to gain further knowledge on the impact of the ligands employed on the reactivity of gold towards (i) the intermolecular oxidative addition of aryl halides and (ii) the possibility of stabilizing high reactive gold(I) intermediates. In the first part of the manuscript, the intermolecular oxidative addition of aryl halides (iodide and bromide) with molecular gold(I) complexes was investigated in detail. We showed that this organometallic elementary step, usually considered to be impossible for gold, is actually a favorable process when an adequate ligand is employed and two different strategies have been elaborated. The first one consists in the use of a bis-phosphine bidentate ligand that forces a bent geometry around gold, whereas the second strategy implicates the use of a hemi-labile bidentate ligand bearing a soft and a hard donor group. Both strategies were found fruitful, and the gold(III) complexes stemming from oxidative addition reactions were characterized by spectroscopic and structural means. In the second part, having in hands two gold(I) complexes that undergo the oxidative addition reaction, we wanted to go beyond this elementary step. In that objective, we constructed a new Au(I)/Au(III) catalytic cycle involving a sequence of Csp2-X oxidative addition, Csp2-H auration and reductive elimination, allowing the first example of gold-catalyzed direct arylation of arenes with aryl halides. Finally, in the last part, we attempted to stabilize and characterize high reactive gold(I) intermediates, like the a-oxo gold(I) carbenes. This electrophilic species is proposed in many catalytic transformations as key intermediates, but has never been isolated or characterized (in solution or in solid state). The use of a bidentate diphosphine ligand allowed the characterization of the a-oxo gold(I) carbene for the first time by means of multinuclear NMR spectroscopy, X-ray diffraction analysis and high resolution mass spectroscopy (ESI+). We then investigated the reactivity of the a-oxo gold(I) carbene towards insertion and cyclopropanation reactions. Interestingly, the reactivity of the generated gold(I) carbenes can be modulated depending on the electronic properties of the aryl ethyl diazoacetate used.