Browsing by Subject "Chemistry Techniques, Synthetic"
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Item Design and Development of New Catalytic Carbon-Carbon Bond Forming Reactions: I. N-Heterocyclic Carbene Based Catalytic Platform for Hauser-Kraus Annulations II. Copper-Catalyzed Selective Allylic Alkylation of Allylic Systems Using Grignard Reagents(2021-05-01T05:00:00.000Z) Sharique, Mohammed; Ready, Joseph M.; Tambar, Uttam; De Brabander, Jef K.; Chen, ChuoThe construction of carbon-carbon bonds has always been at the forefront of synthetic organic chemistry for generating products of greater utilities. Owing to their extraordinary applications in the synthesis of a wide range of therapeutic small molecules and natural products, the design and the development of new and practical synthetic methodologies will always be desirable. Our studies on the development of new catalytic methods to synthesize polycyclic aromatic compounds via a benzannulated reaction and the formation of valuable allylic products from selective allylic alkylation reactions are described. First, the development of N-Heterocyclic carbene catalyzed benzannulation will be discussed based on a venerable reaction called the Hauser-Kraus annulation, developed in 1978 by F. M. Hauser and G. A. Kraus. This reaction has enormous utilization in the synthesis of complex natural products with dihydroxynaphthalene and anthraquinone core structures. However, this method suffers from several drawbacks in a complex molecular setting. We design and develop the first catalytic platform of this traditional reaction based on NHC-mediated umpolung chemistry. The method provides a milder protocol for the synthesis of polycyclic aromatic compounds and also eliminates the drawbacks of the traditional Hauser-Kraus annulation. Secondly, the development of a series of general but highly selective methods for the synthesis of functionalized olefin products from simple unsaturated systems will be described. Unsaturated hydrocarbons are usually low-cost and highly abundant chemical species, making them attractive target substrates for their transformation into synthetically valuable products. However, they pose various challenges during their conversion into a selective product as they possess electronically and sterically similar carbon-hydrogen bonds and often require a highly selective reaction to differentiate between them. The catalytic methods described herein exploit the power of transition-metal catalysis to control the selective formation of allylic alkylation products through a new carbon-carbon bond formation using Grignard reagents. More specifically, two new copper-catalyzed methods will be discussed: (i) a regioselective method for the alkylation of unbiased internal allylic carbonates (ii) a branch selective method for the alkylation of terminal alkenes.Item Enantioselective Total Synthesis of the Kibdelones(2012-07-20) Butler, John R.; Ready, Joseph M.The kibdelones are a family of aromatic polyketides reported in 2006 by Capon and co-workers. These compounds possess potent antibiotic and cytotoxic activities and operate via an unknown and potentially unique mode of action. In order to fully investigate these properties the kibdelones were targeted for total synthesis. Novel methods for heterocycle synthesis and biaryl bond formation were also targeted as part of the synthesis. The kibdelones contain a chlorinated isoquinolinone and stereogenically rich tetrahydroxanthone heterocycles, which make them challenging synthetic targets. To synthesize these compounds a convergent strategy has been developed that splits the molecule into two fragments of similar size. The isoquinolinone moiety was synthesized from amino acid and benzoic acid fragments using a Pomeranz-Fritsch reaction. Our approach to synthesize the tetrahydroxanthone fragment took advantage of an element of latent C2 symmetry present in the kibdelones. Using the Shi-epoxidation this fragment was synthesized in an enantioselective fashion from resorcinol. After joining these fragments with sequential Sonogashira reactions a demanding late stage C-H arylation reaction was used to forge the final C-C bond of the natural product. Importantly, this biaryl bond formation was enabled by the serendipitous discovery of a selective copper-catalyzed iodination reaction. All of these efforts led to the successful 20-step synthesis of (-)-kibdelone C, setting the stage for further biological enquiry of these exciting natural products.Item Synthetic Studies in the Selective Functionalization of Unsaturated Compounds: From Initial Applications in Medicinal Chemistry to General Applications in Unactivated Systems(2016-09-16) Bayeh, Liela Antoinette; Ready, Joseph M.; Tambar, Uttam; De Brabander, Jef K.; Chen, ChuoMedicinal chemistry and reaction development have influenced one another in the field of organic chemistry. The synthesis of therapeutic small molecules often requires the use of practical synthetic methodologies, while reaction development is frequently inspired by the demands of medicinal chemistry. First the development of small molecule inhibitors of hypoxia inducible factors, which are heterodimeric transcription factors that have been implicated in a number of cancer environments, will be discussed. Two scaffolds have been designed and evaluated for their ability to selectively bind within the binding domain of the hypoxia inducible factor-2α isoform and inhibit heterodimerization, with the most potent agonist exhibiting a half maximal inhibitory concentration value of 23 nanomolar. Inspired by the stereospecific mode of action exhibited by the diaryl-tetrazolo-tetrahydropyrimidine-based scaffold of hypoxia inducible factor-2 antagonists, a potential co-catalyst system for the asymmetric synthesis of these derivatives has been identified, utilizing a synergistic combination of a cinchona alkaloid-based primary amine and acid catalysts. While the enantioselectivity of this reaction as it currently stands remains modest, these products can be isolated in up to 96:4 enantiomeric ratio through recrystallization efforts. Secondly, the development of a series of general and efficient methods for the synthesis of functionalized olefin products from simple unsaturated systems will be described. Unfunctionalized olefins and dienes are ideal substrates for chemical synthesis due to their low cost and ease of availability. However they present a variety of challenges when attempting to selectively differentiate between sterically and electronically similar carbon-hydrogen bonds. The processes described herein exploit the ability of sulfurimide and sulfurdiimide reagents to undergo hetero-ene reactions with terminal and internal olefins as well as [4+2] couplings with dienes. These reactions result in reactive intermediates that are utilized in a host of chemical transformations, including [2,3]-rearrangements to generate allylic amines and alcohols, Grignard coupling to generate linear and branched alkylated products, and aminoarylation chemistry. Most notably, a regio- diastereo- and enantioselective synthesis of multifunctional allylic sulfinimides from internal olefins is discussed.Item Synthetic Studies of the Rubellin Natural Products(2020-12-01T06:00:00.000Z) Gartman, Jackson Andrew; De Brabander, Jef K.; Ready, Joseph M.; Chen, Chuo; Tambar, UttamThe effective construction of complex bioactive molecules often requires the development of innovative chemical methods to push the boundaries of organic synthesis. As the utility of available reactions increases, the complexity of possible target molecules increases analogously. This manuscript includes a review of relevant recent natural product syntheses, our studies on the rubellin class of natural products, and our investigation of a rearrangement reaction of reactive iodonium ylide intermediates. First described are select syntheses of complex anthraquinone monomers and dimers within the past 20 years. The scientific community has found deep interest in the anthraquinone class of compounds due to their therapeutic properties and challenging structural elements. Various architecturally beautiful natural products have been successfully synthesized utilizing two main strategies: either an early-stage synthesis of the anthraquinone and further elongation of the system, or a late-stage introduction of the anthraquinone ring moiety. The retrosynthetic disconnections that shape the anthraquinone-installation strategy are emphasized. The second and major chapter describes our studies of the anthraquinone-based rubellin natural products through various synthetic routes and our stereoselective total synthesis of (+)-rubellin C. The synthesis of a rubellin family member represents a synthetic landmark in anthraquinone natural products, as successful total synthesis has evaded the synthetic community since their isolation almost forty years ago. Our synthesis has allowed for preliminary investigation of the reported biological activity of these compounds on the intracellular protein tau, a therapeutic target for Alzheimer's Disease and other neurodegenerative tauopathies. Thirdly, part of our foray into the selective rearrangements of allylic iodonium ylide species is described, in particular our utilization of ligand design to control the selectivity of these rearrangements. We examine the allylic iodonium ylide species, a reactive intermediate that can undergo many uncontrolled processes. In the presence of a metal catalyst and devised ligand, we can modulate the selectivity of this process to generate useful products.