RSC Catalysis Series Jose L. Vicario, Dolores Badía, Luisa Carrillo and Efraim Reyes Organocatalytic Enantioselective Conjugate Addition Reactions A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules CO or ng ja un go ac tea Ata l dy dt i ic tio E nn a Rn et aio cs tie ol e n c st i v e C a V rrillo icar & io R , B e a y d es ía, Organocatalytic Enantioselective Conjugate Addition Reactions A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules RSC Catalysis Series Series Editor: Professor James J Spivey, Louisiana State University, Baton Rouge, USA Advisory Board: Krijn P de Jong, University of Utrecht, The Netherlands, James A Dumesic, University of Wisconsin-Madison, USA, Chris Hardacre, Queen’s University Belfast, NorthernIreland,EnriqueIglesia, Universityof California atBerkeley, USA, Zinfer Ismagilov, Boreskov Institute of Catalysis, Novosibirsk, Russia, JohannesLercher,TUMu¨nchen,Germany,UmitOzkan,OhioStateUniversity, USA, Chunshan Song, Penn State University, USA Titles in the Series: 1: Carbons and Carbon Supported Catalysts in Hydroprocessing 2: Chiral Sulfur Ligands: Asymmetric Catalysis 3: Recent Developments in Asymmetric Organocatalysis 4: Catalysis in the Refining of Fischer-Tropsch Syncrude 5:OrganocatalyticEnantioselectiveConjugateAdditionReactions:APowerful Tool for the Stereocontrolled Synthesis of Complex Molecules How to obtain future titles on publication: A standing order plan is available for this series. A standing order will bring delivery of each new volume immediately on publication. For further information please contact: BookSalesDepartment,RoyalSocietyofChemistry,ThomasGrahamHouse, Science Park, Milton Road, Cambridge, CB4 0WF, UK Telephone: +44 (0)1223 420066, Fax: +44 (0)1223 420247, Email: [email protected] Visit our website at http://www.rsc.org/Shop/Books/ Organocatalytic Enantioselective Conjugate Addition Reactions A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules Edited by Jose L. Vicario, Dolores Badı´a, Luisa Carrillo and Efraim Reyes DepartmentofOrganicChemistry II,University oftheBasqueCountry, Bilbao, Spain RSCCatalysisSeriesNo.5 ISBN:978-1-84973-024-2 ISSN:1757-6725 AcataloguerecordforthisbookisavailablefromtheBritishLibrary r J.L.Vicario,D.Badı´a,L.CarrilloandE.Reyes2010 Allrightsreserved Apartfromfairdealingforthepurposesofresearchfornon-commercialpurposesorfor privatestudy,criticismorreview,aspermittedundertheCopyright,DesignsandPatents Act1988andtheCopyrightandRelatedRightsRegulations2003,thispublicationmaynot bereproduced,storedortransmitted,inanyformorbyanymeans,withouttheprior permissioninwritingofTheRoyalSocietyofChemistryorthecopyrightowner,orinthe caseofreproductioninaccordancewiththetermsoflicencesissuedbytheCopyright LicensingAgencyintheUK,orinaccordancewiththetermsofthelicencesissuedbythe appropriateReproductionRightsOrganizationoutsidetheUK.Enquiriesconcerning reproductionoutsidethetermsstatedhereshouldbesenttoTheRoyalSocietyof Chemistryattheaddressprintedonthispage. TheRSCisnotresponsibleforindividualopinionsexpressedinthiswork. PublishedbyTheRoyalSocietyofChemistry, ThomasGrahamHouse,SciencePark,MiltonRoad, CambridgeCB40WF,UK RegisteredCharityNumber207890 Forfurtherinformationseeourwebsiteatwww.rsc.org Preface Asymmetric organocatalysis has experienced an impressive rebirth in the last few years, with a plethora of new methodologies developed for carrying out enantioselective transformations which up to that moment were only avail- able under transition-metal catalysis. Given the operational and economical advantages associated with this methodology, together with the fact that organocatalysts are environmentally friendly, robust and very often commer- cially available reagents, many research groups worldwide have engaged in active research in this field. In this context, the conjugate addition reaction has attracted a particular interest by the synthetic organic chemists, which has led to an extraordinarily high number of reports dealing with enantio- selective versions of this transformation carried out using small organic molecules as catalysts. Organocatalysts operating by very different mechan- istic profiles have demonstrated their performance when applied to this reac- tion obtaining in many cases outstanding levels of chemical efficiency and stereoselectivity. The conjugate addition reaction is also a particularly inter- esting reaction because of its wide synthetic versatility due to the broad spec- trum of donors and acceptors that may be employed on one hand and also because of its potential to be applied in tandem, domino or cascade reac- tions, resulting in an extremely powerful approach for the preparation of molecules of high complexity in a single step starting from readily available starting materials. This book intends to cover a very hot topic in a rather comprehensive way, includingthe most recent research made inthis fielduntil 2009,presentingthe advancesinthisfieldorganizedaccordingtothemechanisticpathwayinvolved in the activation of the reagents participating in the reaction by the organic catalyst.Wehopethatthisbookwillprovideagoodstate-of-the-artviewtoall organicchemistsworkinginthisfieldandalsotoallwhowishtostartprojects in this area. RSCCatalysisSeriesNo.5 OrganocatalyticEnantioselectiveConjugateAdditionReactions:APowerfulToolforthe StereocontrolledSynthesisofComplexMolecules ByJoseL.Vicario,DoloresBadi´a,LuisaCarrilloandEfraimReyes rJ.L.Vicario,D.Badi´a,L.CarrilloandE.Reyes2010 PublishedbytheRoyalSocietyofChemistry,www.rsc.org v Contents Chapter 1 Introduction 1 1.1 Organocatalysis: an Emerging Field 1 1.2 Historical Evolution of Asymmetric Organocatalysis 5 1.3 Types of Organocatalysts 9 1.4 TheConjugateAdditionReaction:aVeryConvenient Platform for Asymmetric Organocatalysis 11 1.5 On the Organization of This Book 12 References and Notes 13 Chapter 2 Enantioselective Conjugate Addition Reactions via Enamine Activation 18 2.1 Introduction 18 2.1.1 Factors Influencing the Stereocontrol in Michael Additions Proceeding via Enamine Activation 20 2.2 Nitroalkenes as Michael Acceptors 23 2.2.1 Ketones as Michael Donors 23 2.2.2 Aldehydes as Michael Donors 33 2.2.3 Reactions under Non-conventional Methodologies 42 2.3 Enones and Enals as Michael Acceptors 45 2.4 Doubly Activated Olefins as Michael Acceptors 50 2.5 Concluding Remarks 56 References and Notes 56 RSCCatalysisSeriesNo.5 OrganocatalyticEnantioselectiveConjugateAdditionReactions:APowerfulToolforthe StereocontrolledSynthesisofComplexMolecules ByJoseL.Vicario,DoloresBadia,LuisaCarrilloandEfraimReyes rJ.L.Vicario,D.Badia,L.CarrilloandE.Reyes2010 PublishedbytheRoyalSocietyofChemistry,www.rsc.org vii viii Contents Chapter 3 Enantioselective Conjugate Addition Reactions via Iminium Activation 62 3.1 Introduction 62 3.1.1 Factors Influencing the Stereocontrol in Michael Additions Proceeding via Iminium Activation 64 3.2 Michael Reaction 66 3.2.1 a,b-Unsaturated Aldehydes as Michael Acceptors 67 3.2.2 a,b-UnsaturatedKetonesasMichaelAcceptors 80 3.3 Conjugate Friedel–Crafts Alkylation Reaction 87 3.4 Conjugate Hydrogen Transfer Reaction 91 3.5 Conjugate Addition of Heteroatom-based Nucleophiles 94 3.5.1 Oxa-Michael Reactions 94 3.5.2 Sulfa-Michael Reactions 97 3.5.3 Aza-Michael Reactions 99 3.5.4 Phospha-Michael Reactions 103 3.6 Concluding Remarks 106 References and Notes 106 Chapter 4 Enantioselective Conjugate Addition Reactions via Hydrogen-bonding Activation 112 4.1 Introduction 112 4.1.1 Some Relevant Aspects Influencing the StereocontrolinMichaelAdditionsProceeding via Hydrogen-bonding Activation 116 4.2 ConjugateAdditionofStabilizedCarbonNucleophiles 119 4.2.1 Nitroalkenes as Michael Acceptors 120 4.2.2 Enones as Michael Acceptors 139 4.2.3 a,b-Unsaturated Aldehydes as Michael Acceptors 146 4.2.4 AcrylicAcidDerivativesasMichaelAcceptors 149 4.2.5 Other Michael Acceptors 152 4.3 Conjugate Friedel–Crafts Reactions 159 4.4 Conjugate Hydrogen-transfer Reactions 164 4.5 Conjugate Addition of Heteronucleophiles 167 4.5.1 Oxa-Michael Reactions 168 4.5.2 Sulfa-Michael Reactions 171 4.5.3 Aza-Michael Reactions 174 4.5.4 Phospha-Michael Reactions 177 4.6 Concluding Remarks 179 References and Notes 180 Contents ix Chapter 5 Enantioselective Conjugate Addition Reactions via Phase-transfer Catalysis 187 5.1 Introduction 187 5.1.1 Mechanistic Considerations Regarding Michael Additions Proceeding via Phase-transfer Catalysis 190 5.2 ConjugateAdditionofStabilizedCarbonNucleophiles 193 5.2.1 Enones as Michael Acceptors 193 5.2.2 AcrylicAcidDerivativesasMichaelAcceptors 206 5.2.3 a,b-Unsaturated Aldehydes as Michael Acceptors 212 5.2.4 Nitroalkenes as Michael Acceptors 214 5.2.5 Other Michael Acceptors 215 5.3 Conjugate Addition of Heteroatom-centered Nucleophiles 218 5.4 Concluding Remarks 219 References and Notes 219 Chapter 6 Enantioselective Conjugate Addition Reactions Proceeding via Other Types of Activation 222 6.1 Introduction 222 6.2 Enantioselective Conjugate Addition Reactions Catalyzed by N-heterocyclic Carbenes 223 6.2.1 The Intramolecular Enantioselective Stetter Reaction 225 6.2.2 The Intermolecular Enantioselective Stetter Reaction 230 6.3 Enantioselective Conjugate Addition Reactions Catalyzed by Chiral Brønsted Bases 233 6.3.1 Conjugate Addition of Carbon Nucleophiles 234 6.3.2 Conjugate Addition of Heteroatom-based Nucleophiles 236 6.4 Other Miscellaneous Enantioselective Conjugate Addition Reactions 238 6.5 Concluding Remarks 241 References and Notes 241 Chapter 7 Enantioselective Cascade Reactions Initiated by Conjugate Addition 244 7.1 Introduction 244 7.2 CascadeProcessesInitiatedbyConjugateAdditionvia Enamine Activation 245 7.2.1 Cascade Michael/Aldol Reactions 245