Indole derivatives are the most common heterocycle compounds present in nature, for this reason, they have been referred to as 'privileged structures'. In fact, many approved drugs — and natural products — belong to this family. Among indole derivatives, oxindoles have a structural complexity, which have stimulated generations of synthetic chemists to design strategies for assembling these structures, and their enantioselective synthesis is still growing.This book proposes to describe the known enantioselective syntheses of oxindole derivatives. It is divided in six chapters each referring to a specific class of asymmetric oxindole derivatives. After the introduction, Chapter 2 describes all-carbon spirooxindoles; Chapter 3, open chain 3,3-dialkyloxindoles; Chapter 4, 3-substituted-3-aminooxindoles; Chapter 5, 3-substituted-3-hydroxyoxindoles; Chapter 6, 3-hetero-3-substituted oxindoles. It will be a useful tool for synthetic chemists, who assemble total synthesis of natural products, as well as for drug discovery chemists either in academic or in industry R&S laboratories.
"Indole derivatives are the most common heterocycle compounds present in nature, for this reason, they have been referred to as "privileged structures". In fact, many approved drugs - and natural products - belong to this family. Among indole derivatives, oxindoles have a structural complexity, which have stimulated generations of synthetic chemists to design strategies for assembling these structures, and their enantioselective synthesis is still growing. This book proposes to describe the known enantioselective syntheses of oxindole derivatives. It is divided in six chapters each referring to a specific class of asymmetric oxindole derivatives. After the introduction, Chapter 2 describes all-carbon spirooxindoles; Chapter 3, open chain 3,3-dialkyloxindoles; Chapter 4, 3-substituted-3-aminooxindoles; Chapter 5, 3-substituted-3-hydroxyoxindoles; Chapter 6, 3-hetero-3-substituted oxindoles. It will be a useful tool for synthetic chemists, who assemble total synthesis of natural products, as well as for drug discovery chemists either in academic or in industry R&S laboratories."--
Functional diversity and molecular architecture in biologically active oxindoles. Transition metal-catalyzed intramolecular Heck reactions and amide alpha-arylations. Asymmetric rearrangements of O-carbonylated oxindoles and related processes. Amination, hydroxylation, and halogenation reactions of 3-substituted oxindoles. Conjugate addition and alkylation reactions of 3-substituted oxindoles. Asymmetric aldol and Mannich reactions of isatins. Michael additions to isatin-derived electron-deficient alkynes. Nucleophilic substitution reactions of functionalized 3-substituted oxindoles. Enantioselective construction of spirooxindoles by cycloaddition, annulation, and cascade cyclization reactions of methyleneindolinone derivatives. The 3,3-disubstituted-2-oxindole moiety is present in many chiral alkaloids that exhibit interesting biological activities. The enantioselective synthesis of chiral oxindole derivatives has been mainly achieved by asymmetric catalytic methods. In this review we highlight the most important catalytic methods relevant to the synthesis of chiral, non-spirocyclic 3,3-disubstituted oxindoles.
In Chapter One, a catalytic enantioselective method for the synthesis of 3- hydroxy-2-oxindoles is described. 3-Hydroxy-2-oxindoles were synthesized by a nucleophilic addition of electron-rich arenes and aromatic heterocycles to substituted indole-2,3-diones (isatins) catalyzed by scandium(III) and indium(III)-inda-pybox complexes. The use of a bulky chiral ligand hindered the formation of the achiral 3,3-diaryl-2-oxindole side product. Substituted 3-hydroxy-2-oxindoles were formed in high yield and high enantioselectivity (up to 99% ee). In Chapter Two, a method for the synthesis of chiral 3,3-disubstituted-2-oxindoles from a nucleophilic substitution at the stereocenter of a substituted 3-hydroxy-2-oxindole is described. This SN̳1-like process is catalyzed by a Lewis or a Brønsted acid, which eliminates water to form an indolenium ion intermediate. Chiral BINOL-derived phosphoric acids and phosphoramides are promising catalysts for an asymmetric process, as the conjugate base can act as a counteranion that coordinates to the carbocation intermediate to direct an asymmetric nucleophilic addition. Catalyst and solvent effects have been investigated with yields ranging from 68-97%. Preliminary enantioselectivity has been observed and further optimization is underway.
Natural products in the plant and animal kingdom offer a huge diversity of chemical structures that are the result of biosynthetic processes that have been modulated over the millennia through genetic effects. With the rapid developments in spectroscopic techniques and accompanying advances in high-throughput screening techniques, it has become possible to isolate and then determine the structures and biological activity of natural products rapidly, thus opening up exciting new opportunities in the field of new drug development to the pharmaceutical industry. The series also covers the synthesis or testing and recording of the medicinal properties of natural products. Describes the chemistry of bioactive natural products Contains contributions by leading authorities in the field A valuable resource for natural products and medicinal chemistry
The development of regio- and stereoselective methods for the synthesis of oxindoles and spirocyclic oxindoles is important due to the prevalence of these structures in natural products and medicinal agents. This dissertation describes both Lewis acid and organocatalytic strategies for the regio-, diastereo-, and enantioselective synthesis of several classes of 3,3'-oxindoles and 3,3'-spirooxindoles. These strategies are applied to several synthetic transformations including allylsilane annulations, Friedel-Crafts alkylations, and Pictet-Spengler reactions. Chapter one describes an overview of recent methods for the enantioselective synthesis of oxindoles and spirooxindoles with a particular focus on scaffolds relevant to drug discovery. This overview is organized by type of catalyst and strategy in order to compare traditional organometallic and Lewis acid methods with recent organocatalytic methods. This chapter also features a section on multicomponent and cascade reaction strategies. Chapter two describes the development of synthetic methodology using titanium(IV)-catalysis for the selective synthesis of two new classes of spirocyclic oxindoles. In the first section, I present a highly regio- and diastereoselective method for the synthesis of spiro[3,3'oxindoleoxazolines] upon addition of 5-methoxy-2-oxazoles to isatins. In the second section, I present a method for the addition of 5-methoxy-2-aryloxazoles to [alpha],[beta]-unsaturated alkylidene oxindoles to provide access to spiro[3,3'oxindole-1-pyrrolines] with excellent yields and diastereoselectivities. This methodology is also effective for the diastereoselective synthesis of 1-pyrrolines derived from coumarins and simple malonates. Chapter three describes the condensation cyclization between isatins and 5-methoxytryptamine catalyzed by chiral phosphoric acids to provide spirooxindole tetrahydro-[beta]-carboline products in excellent yields and enantioselectivity. A comparison of catalysts provides insight for the reaction scope and factors responsible for efficient catalytic activity and selectivity in these Pictet-Spengler type spirocyclization reactions. In addition I show that chiral phosphoric acids with different 3,3'-substitution on the binaphthyl system and opposite axial chirality afford the spiroindolone product with the same absolute configuration. Chapter four describes a strategy for the efficient two-step synthesis of triazole derivatives of oxindoles and spirooxindoles. Using a common set of N-propargylated isatins, a series of mechanistically distinct stereoselective reactions with different combinations of nucleophiles and catalysts provides access to diverse hydroxy-oxindoles, spiroindolones, and spirocyclic oxazoline structures. The resulting N-propargylated oxindoles are then converted to triazoles using copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. This strategy is used for the synthesis of a 64-member pilot-scale library of diverse oxindoles and spirooxindoles. Chapter five describes the first catalytic asymmetric [3+2] allylsilane annulation for the synthesis of cyclopentanes containing an all-carbon quaternary spirocenter. The annulation reaction is catalyzed with a chiral scandium(III)-indapybox complex where a sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF) anion is essential for catalytic activity and stereoselectivity. Lactone formation affords evidence for an ester stabilized [beta]-silyl carbocation. Further transformations provide access to N-H spirooxindoles and allow transformation of the silyl group to a hydroxyl moiety. This catalyst complex is also effective for the asymmetric Friedel-Crafts conjugate addition of variety of additional pi-nucleophiles (i.e. indoles, pyrroles, anilines) to [alpha],[beta]-unsaturated alkylidene oxindoles. This methodology is also effective for the diastereoselective synthesis of coumarin and simple malonate derivatives.
The series Topics in Heterocyclic Chemistry presents critical reviews on present and future trends in the research of heterocyclic compounds. Overall the scope is to cover topics dealing with all areas within heterocyclic chemistry, both experimental and theoretical, of interest to the general heterocyclic chemistry community. The series consists of topic related volumes edited by renowned editors with contributions of experts in the field. All chapters from Topics in Heterocyclic Chemistry are published Online First with an individual DOI. In references, Topics in Heterocyclic Chemistry is abbreviated as Top Heterocycl Chem and cited as a journal.
Asymmetric synthesis has become a major aspect of modern organic chemistry. The stereochemical properties of an organic compound are often essential to its bioactivity, and the need for stereochemically pure pharmaceutical products is a key example of the importance of stereochemical control in organic synthesis. However, achieving high levels of stereoselectivity in the synthesis of complex natural products represents a considerable intellectual and practical challenge for chemists. Written from a synthetic organic chemistry perspective, this text provides a practical overview of the field, illustrating a wide range of transformations that can be achieved. The book captures the latest advances in asymmetric catalysis with emphasis placed on non-enzymatic methods. Topics covered include: Reduction of alkenes, ketones and imines Nucleophilic addition to carbonyl compounds Catalytic carbon-carbon bond forming reactions Catalytic reactions involving metal carbenoids Conjugate addition reactions Catalysis in Asymmetric Synthesis bridges the gap between undergraduate and advanced level textbooks and provides a convenient point of entry to the primary literature for the experienced synthetic organic chemist.
Progress in Heterocyclic Chemistry (PHC) is an annual review series commissioned by the International Society of Heterocyclic Chemistry (ISHC). Volumes in the series contain both highlights of the previous year’s literature on heterocyclic chemistry and articles on emerging topics of particular interest to heterocyclic chemists. The chapters in Volume 21 constitute a systematic survey of the important original material reported in the literature of heterocyclic chemistry in 2008. Additional articles in this volume review "Biocatalytic approaches to chiral heterocycles" and "Ring-expanded (‘fat’) purines and their nucleoside/nucleotide analogues as broad-spectrum therapeutics." As with previous volumes in the series, Volume 21 apprises academic/industrial chemists and advanced students of developments in heterocyclic chemistry in a convenient format. * Covers the heterocyclic literature published in 2008 * Includes specialized reviews * Features contributions from leading researchers in their fields
This book introduces multi-catalyst systems by describing their mechanism and advantages in asymmetric catalysis. • Helps organic chemists perform more efficient catalysis with step-by-step methods • Overviews new concepts and progress for greener and economic catalytic reactions • Covers topics of interest in asymmetric catalysis including bifunctional catalysis, cooperative catalysis, multimetallic catalysis, and novel tandem reactions • Has applications for pharmaceuticals, agrochemicals, materials, and flavour and fragrance
