Molybdenum and Palladium Catalyzed Asymmetric Allylic Alkylation of Prochiral Nucleophiles PDF Download
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Author: Maurizio Franzini
Publisher:
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Languages : en
Pages : 750
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Author: Maurizio Franzini
Publisher:
ISBN:
Category :
Languages : en
Pages : 750
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Author: Gretchen Marie Schroeder
Publisher:
ISBN:
Category :
Languages : en
Pages : 782
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Author: Gretchen Marie Schroeder
Publisher:
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Category :
Languages : en
Pages : 868
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Author: David Andrew Thaisrivongs
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Languages : en
Pages :
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The research described in this dissertation defines two endeavors into the field of palladium-catalyzed allylic alkylation chemistry: the employment of unstabilized nitrogen-containing aromatic heterocycles as nucleophiles and the use of C--H activation to access [pi]-allyl-palladium electrophiles. With regard to the former program, we demonstrate that 2-methylpyridines, substrates whose corresponding anions are too unstabilized to react productively in palladium-catalyzed asymmetric allylic alkylation (AAA) reactions, form complexes when exposed to boron trifluoride diethyl etherate that can be deprotonated with lithium hexamethyldisilazide to afford competent nucleophiles for AAA processes. Investigations into the reaction mechanism establish that the configuration of the allylic stereocenter of the electrophile is retained, a finding that is consistent with the canonical outer sphere mechanism invoked for palladium-catalyzed allylic substitution processes of stabilized anions. We also show that under modified conditions, this protocol is applicable to the highly regio-, diastereo-, and enantioselective allylic alkylation of 2-substituted pyridines, reactions that form homoallylic stereocenters containing alkyl, aryl, heteroaryl, and nitrogen substituents. When the reaction is correspondingly performed with unsymmetric acyclic electrophiles, both linear and branched products may be obtained regio- and enantioselectively by choosing the appropriate regioisomeric starting material and ligand. We further report that this strategy extends to reactions of a variety of nitrogen-containing aromatic heterocycles, including pyrazines, pyrimidines, pyridazines, quinoxalines, benzoimidazoles, and tetrazoles. The mesityl ester, whose steric bulk prevents competitive deacylation of the electrophile from these nucleophiles, is introduced as a new leaving group in allylic alkylation chemistry. We describe the first general palladium-catalyzed allylic alkylation of 1,4-dienes that proceeds via C--H activation. A broad range of nucleophiles undergo reaction with variously substituted 1,4-dienes under relatively mild conditions, providing direct access to the corresponding 1,3-diene-containing products with high regio- and stereocontrol. This is the first catalytic allylic alkylation that proceeds via C--H activation in the absence of sulfoxide ligands, a discovery that provides for further developments in this chemistry enabled by phosphorus-based ligands. This finding is applied to a new assisted tandem catalytic process that effects sequential palladium(0)-catalyzed allylic alkylations via leaving group ionization and palladium(II)-catalyzed allylic alkylations via C--H activation. By employing an oxidative trigger to convert the initial palladium(0) species to a palladium(II) one, both transformations can be conducted in a single reaction vessel using the same precatalyst. This strategy allows for the introduction of otherwise indistinguishable allyl groups by exploiting complementary catalytic redox cycles. Finally, we detail the discovery and development of the first catalytic enantioselective palladium-catalyzed allylic C--H alkylations, an achievement made possible by a novel class of pyroglutamic-based phosphoramidite ligands. A wide array of sterically and electronically diverse allylarenes undergo allylic substitution by 2-acetyl-1-tetralones to form quaternary carbon stereocenters. Control experiments verify that this palladium-catalyzed process involves direct allylic alkylation, rather than initial allylic C--H acetoxylation. This conceptually and mechanistically distinct strategy averts many of the chemoselectivity issues inherent to traditional methods for the synthesis of enantioenriched allylic substitution products, providing the groundwork for the next generation of palladium-catalyzed allylic alkylation methods.
Author: Karna Lyn Sacchi
Publisher:
ISBN:
Category :
Languages : en
Pages : 266
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Author: Johnathan Edward Schultz
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Languages : en
Pages :
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Herein are described strategies for the asymmetric synthesis of acyclic tetrasubstituted stereocenters using palladium-catalyzed allylic alkylation. In particular prochiral nucleophiles are exploited for the synthesis of acyclic alpha tertiary hydroxyketones, fully substituted nitroalkanes, and all-carbon quaternary stereocenters. The problem of O-alkylation in benzylic nitronate synthesis was overcome by the use of a decarboxylative asymmetric allylic alkylation of allyl alpha nitroesters. Extensive screening of reaction conditions revealed a unique ligand and solvent combination that proved crucial for achieving high chemo- and enantioselectivity in this challenging reaction. Substrates were readily synthesized via a combinatorial cross-Claisen / alpha arylation protocol, and the method was highlighted by chemoselective functional group interconversions of a highly elaborated substrate. Boronic acids were exploited as templates of ene-diolate systems to solve a longstanding problem of direct asymmetric C-alkylation of alpha hydroxyketones. This process was rendered chemo-, regio-, and enantioselective in allylation reactions, while point and axial chirality were efficiently set in allylic alkylations of racemic allene substrates via a dynamic kinetic asymmetric transformation. This method represents one of the first examples where point and axial chirality are effectively set in allylic alkylation. As a follow-up to this work, enol boranes were found to be effective pronucleophiles in palladium-catalyzed allylic alkylation reactions. A 1,4-hydroboration reaction was exploited for the thermal generation of regio-defined enol boranes, and a unique electron-deficient ligand was found to exhibit differential reactivity in the subsequent alkylation reaction. This chemistry was further extended to provide a room temperature alkylation of ester derived enol boranes, in particular, unactivated esters. A preparative application was demonstrated in the synthesis of acyclic all-carbon quaternary stereocenters, where the stereoselectivity was a function of the identities of a chiral auxiliary, a chiral ligand, and a designer leaving group. It is hoped that this chemistry may spur broader interest in metal-catalyzed reactions of enol boranes.
Author: Lara Christine Czabaniuk
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Languages : en
Pages :
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This dissertation details research in the development of palladium-catalyzed asymmetric benzylation. This methodology expands the scope of palladium-catalyzed substitution chemistry and represents a novel means for synthesizing chiral molecules via addition of a benzyl group. Prochiral nucleophiles, wherein enantiodiscrimination occurs during nucleophilic attack on a cationic pi-benzyl-palladium intermediate, are utilized in the reaction with achiral electrophiles. Initial investigations into use of 1,3-dicarbonyls as nucleophiles revealed that high reactivity could be achieved with methyl carbonate electrophiles under palladium catalysis at high reaction temperature. Asymmetric induction was achieved using a chiral Trost-style bisphosphine ligand, which proved to be superior to other chiral phosphine ligands. Optimization with respect to various reaction parameters was performed, and moderate enantioselectivity with a number of 1,3-diketone nucleophiles was realized. We next describe the use of oxindoles, privileged scaffolds in medicinal chemistry, as nucleophiles for asymmetric benzylation methodology. Initial screening revealed the importance of the substituent on the nitrogen atom, with a free N-H yielding the highest enantioselectivity. Investigation of ligand, solvent, temperature, and additive effects identified a set of conditions to provide high yield and enantioselectivity for the reaction between 3-aryl oxindoles and benzylic methyl carbonate electrophiles. A number of substitution patterns were well-tolerated on the oxindole moiety. The electrophile scope included naphthalene-, indole-, benzofuran-, and furan-substituted electrophiles. This research is the first reported palladium-catalyzed asymmetric benzylation of a prochiral nucleophile. The reaction proceeds under mild conditions and generates a quaternary stereocenter. Benzylic methyl carbonate electrophiles were found to be unreactive. Modest conversion of benzylic phosphates was observed, although with moderate enantioselectivity. Azlactones represent a masked amino acid, and were studied as nucleophiles in asymmetric benzylation to provide precursors to chiral quaternary amino acids. Conditions for highly asymmetric benzylation of azlactone nucleophiles with naphthyl and heterocyclic methyl carbonate electrophiles were developed using a Trost-style ligand for asymmetric induction. Investigation into expansion of scope to include monocyclic benzylic electrophiles was also conducted on these highly reactive nucleophiles. Modest reactivity was observed with carbonate electrophiles; phosphate electrophiles, which contain a more labile leaving group, found greater success in the transformation. A diethyl phosphate leaving group was employed for electron-rich aryl rings, while a diphenyl phosphate was required for high reactivity of electron-neutral substrates. The utility of the methodology was demonstrated in a synthesis of alpha-methyl-D-dopa via a one-step azlactone hydrolysis.
Author: Takahiko Akiyama
Publisher: John Wiley & Sons
ISBN: 1119736412
Category : Science
Languages : en
Pages : 798
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Catalytic Asymmetric Synthesis Seminal text presenting detailed accounts of the most important catalytic asymmetric reactions known today This book covers the preparation of enantiomerically pure or enriched chemical compounds by use of chiral catalyst molecules. While reviewing the most important catalytic methods for asymmetric organic synthesis, this book highlights the most important and recent developments in catalytic asymmetric synthesis. Edited by two well-qualified experts, sample topics covered in the work include: Metal catalysis, organocatalysis, photoredox catalysis, enzyme catalysis C–H bond functionalization reactions Carbon–carbon bond formation reactions, carbon–halogen bond formation reactions, hydrogenations, polymerizations, flow reactions Axially chiral compounds Retaining the best of its predecessors but now thoroughly up to date with the important and recent developments in catalytic asymmetric synthesis, the 4th edition of Catalytic Asymmetric Synthesis serves as an excellent desktop reference and text for researchers and students, from upper-level undergraduates all the way to experienced professionals in industry or academia.
Author: James Thomas Masters
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Languages : en
Pages :
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The continued demand for efficient chemo-, regio-, and stereoselective organic transformations motivates the development of new chemical reactions. Transition metal catalysis represents a powerful method for the construction of carbon-carbon, carbon-hydrogen, and carbon-heteroatom bonds in a highly selective fashion. This dissertation describes the development of several new transition metal-catalyzed organic reactions useful in the preparation of various chiral small molecules, including both fundamental organic "building block" compounds and structurally complex natural products and pharmaceutical agents. We report a new strategy for the synthesis of chiral beta-alkynyl esters, ketones, and sulfones via sequential palladium-catalyzed carbon-carbon bond formation and copper-catalyzed carbon-hydrogen bond formation. The process is operationally straightforward, compatible with a broad range of substrates, and delivers the targets in high yields with excellent levels of enantioselectivity. It is compatible with both oxygen and nitrogen functionality, and this enabled the rapid elaboration of the products into a diverse set of chiral heterocycles. The sequential catalysis protocol was employed in a concise, enantioselective synthesis of AMG 837, a potent agonist of G-protein coupled receptor 40. Recognizing both the biological relevance of chiral alkaloids and the synthetic challenges associated with the construction of quaternary, all-carbon stereocenters, we pursued a palladium-catalyzed asymmetric allylic alkylation that effected carbon-carbon bond formation on prochiral oxindole nucleophiles. Although prior research has demonstrated that allylic alkylation reactions of geminal dicarboxylate electrophiles typically yield branched products as the result of ipso-addition, we identify conditions wherein oxindoles react with a dipivaloyl electrophile to afford linear enol pivalate compounds. A mild hydrolysis reaction converts these products into the aldehyde that formally results from asymmetric conjugate addition to acrolein, a challenging transformation with limited literature precedent. These adducts are established precursors to tricyclic alkaloid scaffolds of pharmaceutical interest. Chiral gamma-heteroatom-substituted cycloalkenones are well-established organic "building blocks" that are widely used in the synthesis of complex molecules. The exposure of meso-1,4-allylic dibenzoates to chiral phosphine-ligated palladium salts in the presence of a potassium nitronate nucleophile promotes a unique oxidative desymmetrization reaction. This process yields enantiopure gamma-benzoyloxy cyclopentenones, cyclohexenones, and cycloheptenones. We describe the elaboration of these products into diverse, enantioenriched oxygen- and nitrogen-substituted cycloalkenones via subsequent palladium-catalyzed allylic alkylation reactions involving heteroatom nucleophiles. Separately, we employ enantiopure gamma-benzoyloxy cyclohexenones in short, asymmetric syntheses of enantio- and diastereomerically diverse epoxyquinoid natural products. We further highlight the utility of palladium catalysis in complex molecule synthesis through the development of a unique, intramolecular carbon-carbon bond-forming reaction that generates a strained enyne and through an asymmetric formal synthesis of aliskiren, a renin inhibitor used in the treatment of hypertension.
Author: Mark Lautens
Publisher: Ann Arbor, Mich. : University Microfilms International
ISBN:
Category :
Languages : en
Pages : 588
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