Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules

Accounts of Chemical Research, Journal Year: 2015, Volume and Issue: 48(3), P. 740 - 751

Published: Feb. 25, 2015

The ever-present demand for drugs with better efficacy and fewer side effects continually motivates scientists to explore the vast chemical space. Traditionally, medicinal chemists have focused much attention on achiral or so-called "flat" molecules. More recently, has shifted toward molecules stereogenic centers since their three-dimensional structures represent a larger fraction of space number superior properties compared flat aromatic compounds. Quaternary stereocenters, in particular, add greatly three-dimensionality novelty molecule. Nevertheless, synthetic challenges building quaternary stereocenters largely prevented implementation drug discovery. lack effective broadly general methods enantioselective formation simple molecular scaffolds prompted us investigate new chemistry develop innovative tools solutions. In this Account, we describe three approaches constructing stereocenters: nucleophilic substitution 3-halooxindoles, conjugate addition boronic acids cyclic enones, allylic alkylation enolates. first approach, malonic ester nucleophiles attack electrophilic mediated by copper(II)-bisoxazoline catalyst. A variety oxindoles containing benzylic stereocenter can be accessed through method. However, it is only applicable specialized 3,3-disubstituted oxindole system. To access more context, turned our carbon α,β-unsaturated carbonyl acceptors. We discovered that presence catalytic palladium-pyridinooxazoline complex, arylboronic smoothly β-substituted enones furnish ketones β-benzylic high yields enantioselectivities. reaction compatible wide range acids, β-substituents, ring sizes. Aside from challenging motif not adjacent an group. Such but are difficult form asymmetric catalysis. address greater challenge, motivated reward, entered field palladium-catalyzed prochiral enolate about decade ago. On basis Tsuji's work, which solved issue positional selectivity unsymmetrical ketones, phosphinooxazoline ligand effectively rendered enantioselective. Extensive investigations then revealed exhibits broad scope accepts substrate classes, each its unique advantage applications. diverse array compounds bearing α-quaternary obtained excellent enantioselectivities, possibilities yet explored. As alternative palladium catalysis, also studied iridium-catalyzed alkylations generate vicinal tertiary single transformation. Overall, these provide small molecule blocks stereocenter, applied various scaffolds, tolerate functional groups. envision reported Account will increasingly useful discovery design.

Language: Английский

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Iridium-Catalyzed Asymmetric Allylic Substitution Reactions

Chemical Reviews, Journal Year: 2018, Volume and Issue: 119(3), P. 1855 - 1969

Published: Dec. 24, 2018

In this review, we summarize the origin and advancements of iridium-catalyzed asymmetric allylic substitution reactions during past two decades. Since first report in 1997, Ir-catalyzed have attracted intense attention due to their exceptionally high regio- enantioselectivities. been significantly developed recent years many respects, including ligand development, mechanistic understanding, substrate scope, application synthesis complex functional molecules. an explicit outline ligands, mechanism, scope nucleophiles, applications is presented.

Language: Английский

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Metal-catalyzed asymmetric conjugate addition reaction: formation of quaternary stereocenters

Chemical Communications, Journal Year: 2010, Volume and Issue: 46(39), P. 7295 - 7295

Published: Jan. 1, 2010

All-carbon quaternary stereocenters are ubiquitous motifs in biological products and pharmaceutical agents. However, due to sterical reasons, these centers not always easily accessible. The metal-catalyzed conjugate addition reaction trisubstituted conjugated substrates presents a viable methodology create centers. In this article, different ways of activating the system towards nucleophilic will be described. An overview given on types that accessible through reaction.

Language: Английский

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Rhodium-catalysed asymmetric hydrogenation as a valuable synthetic tool for the preparation of chiral drugs

Chemical Society Reviews, Journal Year: 2012, Volume and Issue: 42(2), P. 728 - 754

Published: Nov. 7, 2012

During the last few decades, rhodium-catalysed asymmetric hydrogenation of diverse alkene classes has emerged as a powerful synthetic tool in pharmaceutical industry, contributing to manufacturing chiral drugs, recent drug candidates for clinical trials, and major precursors drugs. Numerous efficient rhodium complexes, most which are derived from enantiopure phosphorus ligands, have been employed preparation drugs intermediates thereof. This review article is intended provide an updated overview striking contributions this field, organised according substrate class: acrylate derivatives, itaconate α-substituted enamides, α-arylenol acetates, minimally functionalised olefins.

Language: Английский

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Mechanisms of Nucleophilic Organocopper(I) Reactions

Chemical Reviews, Journal Year: 2011, Volume and Issue: 112(4), P. 2339 - 2372

Published: Nov. 23, 2011

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTMechanisms of Nucleophilic Organocopper(I) ReactionsNaohiko Yoshikai† and Eiichi Nakamura*‡View Author Information† Division Chemistry Biological Chemistry, School Physical Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore‡ Department Science, The University Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan*E-mail: [email protected]Cite this: Chem. Rev. 2012, 112, 4, 2339–2372Publication Date (Web):November 23, 2011Publication History Received28 June 2011Published online23 November inissue 11 April 2012https://pubs.acs.org/doi/10.1021/cr200241fhttps://doi.org/10.1021/cr200241freview-articleACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views22689Altmetric-Citations347LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum full text article downloads since 2008 (both PDF HTML) across all institutions individuals. These metrics regularly updated to reflect usage leading up last few days.Citations number other articles citing this article, calculated by Crossref daily. Find more information about citation counts.The Altmetric Attention Score is a quantitative measure attention that research has received online. Clicking on donut icon will load page at altmetric.com with additional details score social media presence for given article. how calculated. Share Add toView InAdd Full Text ReferenceAdd Description ExportRISCitationCitation abstractCitation referencesMore Options onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting SUBJECTS:Addition reactions,Conjugate acid-base pairs,Ligands,Reagents,Substitution reactions Get e-Alerts

Language: Английский

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An Ir/Zn Dual Catalysis for Enantio- and Diastereodivergent α-Allylation of α-Hydroxyketones

Journal of the American Chemical Society, Journal Year: 2016, Volume and Issue: 138(35), P. 11093 - 11096

Published: Aug. 22, 2016

An Ir/Zn dual catalysis has been developed for the enantio- and diastereodivergent α-allylation of unprotected α-hydroxyketones under mild conditions, in absence any additional base. The cooperative action a chiral iridium complex derived from phosphoramidites Zn-ProPhenol is most likely responsible its high reactivity, excellent enantioselectivity (up to >99% ee), good diastereoselectivity >20:1 dr). All four product stereoisomers could be prepared same set starting materials identical conditions by simple selection appropriate catalyst combinations.

Language: Английский

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Iridium-Catalyzed Asymmetric Synthesis of Functionally Rich Molecules Enabled by (Phosphoramidite,Olefin) Ligands

Accounts of Chemical Research, Journal Year: 2019, Volume and Issue: 52(9), P. 2657 - 2672

Published: June 19, 2019

ConspectusThe catalytic, asymmetric synthesis of complex molecules has been a core focus our research program for some time because developments in the area can have an immediate impact on identification novel strategies value-added molecules. In concert with this central interest, we emphasized design ligand scaffolds as tactic to discover and develop chemistry overcome well-recognized synthetic challenges. Based group's work chiral pool-derived diolefin ligands, designed implemented class hybrid (phosphoramidite,olefin) which combines properties both phosphoramidite olefin motifs impact, fine-tune, even override inherent reactivity metal center. Specifically, utilized these unique modifying ligands address several recognized limitations field iridium-catalyzed, allylic substitution. The methods documented typically employ branched, unprotected alcohols substrates obviate need rigorous exclusion air moisture.Following Takeuchi's seminal report demonstrating high aptitude Ir(I)-phosphite catalysts branch-selective substitution, concerted efforts from numerous laboratories led broadening utility reaction class. first section Account outlines process leading discovery unprecedented its validation iridium-catalyzed amination alcohols. This continues involving heteroatom-based nucleophiles within inter- intramolecular etherification, thioetherification spiroketalization processes. second highlights use readily available carbon possessing sp, sp2, sp3 hybridization series enantioselective carbon–carbon bond-forming reactions. We describe how alkylzinc, allylsilane, classes organotrifluoroborate be coupled enantioselectively enable construction key including 1,5-dienes, 1,4-dienes, 1,4-enynes. Since electronic steric renders (η3-allyl)-Ir(III) intermediate highly electrophilic, weak such alkyl olefins used. also show that more nucleophilic alkene enamines situ generated ketene acetals smoothly participate substitution reactions yield valuable piperidines γ,δ-unsaturated esters, respectively.The concept stereodivergent dual catalysis, synergistically amine catalysis iridium furnish α-allylated aldehydes containing two independently controllable stereocenters is then discussed. enabled independent, stereoselective all four possible product stereoisomers single set starting materials, was highlighted Δ9-tetrahydrocannabinol. concludes overview organometallic mechanistic studies regarding relevant intermediates catalytic cycle These allowed us better understand origin characteristics exhibited by catalyst comparison related systems.

Language: Английский

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Stereodivergent Synthesis of α,α-Disubstituted α-Amino Acids via Synergistic Cu/Ir Catalysis

Journal of the American Chemical Society, Journal Year: 2018, Volume and Issue: 140(4), P. 1508 - 1513

Published: Jan. 5, 2018

Cu/Ir dual catalysis has been developed for the stereodivergent α-allylation of aldimine esters. The method enables preparation a series nonproteinogenic α-amino acids (α-AAs) bearing two contiguous stereogenic centers in high yield with excellent stereoselectivity. All four product stereoisomers could be obtained from same set starting materials via pairwise combination chiral catalysts. Notably, one-pot protocol successfully applied bimetallic complexes to simplify manipulation catalysis. This further utilized construction key intermediate bioactive pyrrolidine derivative and concise synthesis plant growth regulator (2S,3S)-2-amino-3-cyclopropylbutanoic acid.

Language: Английский

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Applications of Iridium-Catalyzed Asymmetric Allylic Substitution Reactions in Target-Oriented Synthesis

Accounts of Chemical Research, Journal Year: 2017, Volume and Issue: 50(10), P. 2539 - 2555

Published: Sept. 22, 2017

ConspectusMetal catalyzed allylic substitution is a cornerstone of organometallic and synthetic chemistry. Enantioselective versions have been developed with catalysts derived from transition metals, most notably molybdenum, nickel, ruthenium, rhodium, iridium, palladium, copper. The palladium- the iridium-catalyzed turned out to be particularly versatile in organic synthesis because very broad scope nucleophile great functional group compatibility. Assets reaction are formation branched, chiral products simple monosubstituted substrates, high degrees regio- enantioselectivity, use modular, readily available ligands. possibility carbon, nitrogen, oxygen, sulfur compounds as well fluoride nucleophiles allows wide range building blocks prepared.Our Account begins presentation fundamental schemes We will focus our discussion on reactions promoted by phosphoramidite ligands, though numerous ligands employed. subsequent section presents brief overview mechanism experimental conditions. Two emerged. In type 1 (introduced 1997), linear esters commonly used substrates under basic 2 2007), environmentally friendly branched alcohols can reacted acidic conditions; occasionally, derivatives also applied. A unique feature that highly electrophilic intermediates brought weakly activated alkenes.The text ordered according strategies followed transform desired targets, which natural or drugs. Syntheses starting an intermolecular discussed first. Some fairly complex for example, potent nitric oxide inhibitor (−)-nyasol drug (−)-protrifenbute, synthesized via less than five steps materials.Most targets cyclic compounds. Intermolecular ring closing metathesis powerful strategy their synthesis. Highlights stereodivergent syntheses Δ9-tetrahydrocannabinols (THC), wherein iridium- organocatalysis combined (dual catalysis). combination alkylation Diels–Alder was utilized synthesize ketide apiosporic acid fesoterodine (Toviaz). Sequential amination, hydroboration Suzuki–Miyaura coupling generates enones suitable conjugate addition reactions; this employed variety alkaloids, poison frog alkaloid (+)-cis-195A (pumiliotoxin C).Intramolecular substitutions offer interesting possibilities build up stereochemical complexity short routes. For diastereoselective cyclizations compounds, substrate control overruled catalyst order generate cis- trans-isomers selectively given precursor. This approach prepare piperidine pyrrolidine alkaloids. Finally, polycyclic structures, including structurally unusual indolosesquiterpenoid mycoleptodiscin A, generated diastereo- enantioselectively olefins polyene electron-rich arenes, such indoles, dearomatization reactions.

Language: Английский

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Catalytic Asymmetric Synthesis of Allylic Alcohols and Derivatives and their Applications in Organic Synthesis

Angewandte Chemie International Edition, Journal Year: 2013, Volume and Issue: 52(7), P. 1890 - 1932

Published: Jan. 14, 2013

Abstract Allylic alcohols represent an important and highly versatile class of chiral building blocks for organic synthesis. This Review summarizes the plethora methods developed catalytic asymmetric synthesis enantioenriched allylic alcohols. These include: dynamic kinetic resolution (DKR/DKAT), nucleophilic 1,2‐addition to carbonyl groups, substitution, oxidation CH bonds, addition O nucleophiles π systems, reduction unsaturated compounds, alternative route from propargylic Furthermore, these processes are exemplified by their applications in syntheses complex molecules such as natural products potential therapeutic agents.

Language: Английский

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