Browsing by Subject "Alkenes"
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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 Preparation of Substituted Enol Derivatives from Terminal Alkynes and Progress Toward the Total Synthesis of Nigricanoside A(2011-02-01) DeBergh, John Robbins; Ready, Joseph M.This manuscript consists of two chapters. The first chapter describes the preparation of stereodefined enol derivates of alpha-branched aldehydes from terminal alkynes. Specifically, alkenyl alanes, derived from the methylalumination of alkynes, are shown to be efficiently oxygenated with peroxyzinc species. The resulting metallo-enolate may be trapped with benzoic anhydride, acetic anhydride, and TESOTf to generate E-trisubstituted enol esters and silanes. Traditional approaches to these types of olefins involve enolization of aldehydes; these methods are often inefficient and generally afford mixtures of olefin stereoisomers. Therefore, the methodology presented Chapter One represents a conceptually novel and useful strategy. The development and scope of the methylalumination-oxygenation reaction is discussed along with applications of the enol derivatives in the context of asymmetric and natural product synthesis. Finally, the alkenyl alane intermediates are shown to be efficiently aminated to afford ene-hydrazine products. The second chapter involves the progress towards the asymmetric synthesis and structural assignment of nigricanoside A, a potent antimitotic glycolipid isolated from marine green algae. A convergent synthetic route is presented along with an analysis the natural product’s relative and absolute stereochemistry. Various diastereomers of orthogonally protected subunits of nigricanoside A were prepared through vinyl-metal additions to alpha-hydroxy aldehydes. The chapter includes attempts to join the subunits through etherification reactions as well as descriptions of future strategies to effect etherification.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 The Synthetic Utility of Enol Derivatives and the Directed Aryltitanation of Homoallylic and Allylic Alcohols(2012-07-20) Lee, Kathleen Marie Spivey; Ready, Joseph M.This dissertation is organized in three parts. First, enol derivatives represent important building blocks for organic synthesis. Often their olefin geometry directly translates into product diastero- and enantioselectivity. Thus, stereodefined enol benzoates are subjected to the Sharpless Asymmetric Dihydroxylation to form enantiomerically enriched alpha-hydroxy aldehydes. Due to their instability, these alpha-hydroxy aldehydes are further transformed in situ to demonstrate their utility in organic synthesis. The second and third parts address the carbometalation of two types of alkenes. While the carbometalation of alkynes is a widely used transformation, the corresponding transformation for alkenes is less developed. Directing groups, such as homoallylic and allylic alcohols, may help overcome the poor reactivity of alkenes towards carbometalation. Herein the alcohols direct a highly diastereoselective aryltitanation to the proximal carbon–carbon double bond. Reactions with homoallylic alcohols result in stereospecific aryl incorporation at the terminal carbon of the double bond while the reactions with the allylic alcohol incorporate the aryl group proximal to the alcohol and generate two new sp3 centers.