Edited by

Alexandre Alexakis, Norbert Krause, and

Simon Woodward

Copper-Catalyzed Asymmetric Synthesis

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Edited by Alexandre Alexakis, Norbert Krause, andSimon Woodward

Copper-Catalyzed Asymmetric Synthesis

The Editors

Prof. Dr. Alexandre AlexakisUniversity of GenevaDept. of Organic ChemistryPostfach 301211 Geneve 4Switzerland

Prof. Dr. Norbert KrauseUniversity DortmundOrganic Chemistry IIOtto-Hahn-Str. 644227 DortmundGermany

Prof. Dr. Simon WoodwardUniversity Of NottinghamSchool of ChemistryUniversity ParkNottingham NG7 2RDUnited Kingdom

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V

Contents

List of Contributors XIII

Introduction 1Alexandre Alexakis, Norbert Krause, and Simon Woodward

1 The Primary Organometallic in Copper-Catalyzed Reactions 3Simon Woodward

1.1 Scope and Introduction 31.2 Terminal Organometallics Sources Available 41.3 Coordination Motifs in Asymmetric Copper Chemistry 51.3.1 Classical Cuprate Structure and Accepted Modes of Reaction 61.3.1.1 Conjugate Addition 61.3.1.2 SN2′ Allylation Reactions 91.3.2 Motifs in Copper-Main Group Bimetallics and Substrate Binding 91.4 Asymmetric Organolithium–Copper Reagents 111.5 Asymmetric Grignard–Copper Reagents 131.6 Asymmetric Organozinc–Copper Reagents 161.7 Asymmetric Organoboron–Copper Reagents 201.8 Asymmetric Organoaluminium–Copper Reagents 231.9 Asymmetric Silane and Stannane Copper-Promoted Reagents 251.10 Conclusions 28

References 29

2 Copper-Catalyzed Asymmetric Conjugate Addition 33Alexandre Alexakis, Norbert Krause, and Simon Woodward

2.1 Introduction 332.2 Conjugate Addition 352.2.1 The Nucleophile 352.2.2 The Copper Salt 372.2.3 The Ligand 372.2.4 Scope of Michael Acceptors 402.2.4.1 Enones 42

VI Contents

2.2.4.2 Enals 462.2.4.3 Nitroalkenes 472.2.4.4 α,β-Unsaturated Amide and Ester Derivatives 482.2.4.5 Other Michael Acceptors 522.2.5 Formation of All-Carbon Quaternary Stereocenters 532.3 Trapping of Enolates 57

References 63

3 Copper-Catalyzed Asymmetric Conjugate Addition and AllylicSubstitution of Organometallic Reagents to Extended Multiple-BondSystems 69Matthieu Tissot, Hailing Li, and Alexandre Alexakis

3.1 Introduction 693.2 Copper-Catalyzed Asymmetric Conjugate Addition (ACA) to

Polyconjugated Michael Acceptors 693.2.1 Background 693.2.2 1,6 Selectivity in ACA to Polyconjugated Systems 723.2.3 1,4 Selectivity in ACA to Polyconjugated Systems 753.3 Copper-Catalyzed Asymmetric Allylic Substitution on Extended

Multiple-Bond Systems 803.3.1 Background 803.3.2 Copper-Catalyzed Enantioselective Allylic Substitution on Extended

Multiple-Bond Systems 823.4 Conclusion 83

References 83

4 Asymmetric Allylic Alkylation 85Olivier Basle, Audrey Denicourt-Nowicki, Christophe Crevisy, andMarc Mauduit

4.1 Introduction 854.2 Nucleophiles in Enantioselective Process Development 874.2.1 Grignard Nucleophiles 874.2.2 Diorganozinc Nucleophiles 954.2.3 Triorganoaluminium Nucleophiles 984.2.4 Organoboranes Nucleophiles 984.2.5 Organolithium Nucleophiles 1014.3 Functionalized Substrates 1014.3.1 Trisubstituted Substrates 1014.3.2 Ester Derivatives 1034.3.3 Heterofunctionalized Substrates 1054.3.4 Vinylic Boronates and Silanes 1084.3.5 Substrates Bearing Two Leaving Groups (1,4 or 1,1′) 1104.3.6 Enyne-Type Substrates 1104.4 Desymmetrization of meso-Allylic Substrates 112

Contents VII

4.4.1 Polycyclic Hydrazines, Symmetric Allylic Epoxides, OxabicyclicAlkenes 112

4.4.2 Cyclic Allylic Bis(Diethyl phosphates) 1124.4.3 Miscellaneous Desymmetrization 1134.5 Kinetic Resolution Processes 1154.5.1 Allylic Epoxides and Aziridines, Oxabicyclic Alkenes, Bicyclic

Oxazines 1154.5.2 Stereodivergent Kinetic Resolution on Acyclic Allylic Halides 1154.6 Direct Enantioconvergent Transformation 1174.7 Conclusion and Perspectives 118

References 119

5 Ring Opening of Epoxides and Related Systems 127Mauro Pineschi

5.1 Introduction 1275.2 Copper-Catalyzed Asymmetric Ring Opening of Epoxides with

Amines 1285.3 Copper-Catalyzed Asymmetric Ring Opening of Epoxides and

Aziridines with Organometallic Reagents 1325.3.1 Copper-Catalyzed Kinetic Resolution of Racemic Allylic Epoxides and

Allylic Aziridines with Dialkylzincs 1355.3.2 Copper-Catalyzed Enantioselective Desymmetrization of meso-Allylic

Epoxides with Dialkylzincs 1385.3.3 Copper-Catalyzed Regiodivergent Kinetic Resolution of Racemic

Allylic Epoxides with Dialkylzincs 1415.3.4 Copper-Catalyzed Asymmetric Ring Opening of Racemic Strained

Three-Membered Compounds with Organoaluminium and GrignardReagents 144

5.4 Copper-Catalyzed Asymmetric Ring Opening of HeterobicyclicSystems with Organometallic Reagents 147

5.5 Conclusions 151References 151

6 Carbon–Boron and Carbon–Silicon Bond Formation 157Masaya Sawamura and Hajime Ito

6.1 Introduction 1576.2 C–B Bond Formation Reactions 1576.2.1 Boron Reagents and Copper(I)–Boryl Species 1576.2.2 Allylic C–B Couplings to Produce Allylboron Compounds and Related

Reactions 1596.2.3 β-Boration of α,β-Unsaturated Carbonyl Compounds 1626.2.4 Hydroboration of Nonpolar Alkenes 1686.3 C–Si Bond Formation Reactions 1726.3.1 Allylic C–Si Coupling Producing Allylsilanes 1726.3.2 β-Silylation of α,β-Unsaturated Carbonyl Compounds 173

VIII Contents

6.4 Summary 175References 175

7 CuH in Asymmetric Reductions 179Bruce H. Lipshutz

7.1 Introduction 1797.2 Asymmetric Conjugate Reductions 1827.2.1 α,β-Unsaturated Sulfones 1827.2.2 α,β-Unsaturated Nitriles and Nitroolefins 1837.2.3 α,β-Unsaturated Ketones and Esters 1847.3 Asymmetric 1,2-Additions 1897.3.1 Aryl Ketones 1897.3.2 Dialkyl Ketones 1937.3.3 α,β-Unsaturated Ketones 1947.4 Heterogeneous Catalysis 1967.4.1 Charcoal 1967.4.2 Nanocrystalline CuO 1977.4.3 Cu–Al Hydrotalcite 1977.4.4 Copper Ferrite Nanoparticles 1987.5 Conclusions and Perspective 199

References 199

8 Asymmetric Cyclopropanation and Aziridination Reactions 203Andre B. Charette, Helene Lebel, and Marie-Noelle Roy

8.1 Introduction 2038.2 Asymmetric Cyclopropanation 2038.2.1 Intermolecular Cyclopropanation Using Metal Carbenes 2038.2.1.1 Using Unsubstituted Copper Carbenes: Diazomethane 2058.2.1.2 Using Copper Carbenes Bearing One Electron-Withdrawing

Group 2068.2.1.3 Using Metal Carbenes Bearing Two Electron-Withdrawing

Groups 2138.2.1.4 Using Donor/Acceptor Copper Carbenes 2148.2.2 Intramolecular Cyclopropanation Using Copper Carbenes 2168.3 Asymmetric Aziridination 2198.3.1 Intermolecular Aziridination Using Copper Nitrenes 2198.3.1.1 Of Terminal Styrene Derivatives 2228.3.1.2 Of β-Substituted Styrene Derivatives 2258.3.1.3 Of Cyclic Styrene Derivatives 2278.3.1.4 Of Cinnamate Derivatives 2278.3.1.5 Of Chalcone Derivatives 2308.3.1.6 Of Terminal Aliphatic Alkenes 2338.3.2 Intramolecular Aziridination Using Copper Nitrenes 2338.4 Conclusion 234

References 234

Contents IX

9 Copper-Catalyzed Asymmetric Addition Reaction of Imines 239Kiyoshi Tomioka, Ken-ichi Yamada, and Yasutomo Yamamoto

9.1 Introduction 2399.1.1 Asymmetric Alkylation of Imines with Organometallic Reagents 2399.1.2 Possibility of Catalytic Reaction 2409.2 Copper-Catalyzed Asymmetric Addition Reaction of Dialkylzinc to

Imines 2419.2.1 Addition to C=N Double Bonds of Imines 2419.2.2 Conjugate Addition to α,β-Unsaturated Imines 2479.3 Copper-Catalyzed Asymmetric Allylation, Arylation, and Alkynylation

Reactions of Imines 2499.3.1 Copper-Catalyzed Asymmetric Allylation of Imines 2499.3.2 Copper-Catalyzed Asymmetric Arylation of Imines 2509.3.3 Copper-Catalyzed Asymmetric Alkynylation of Imines 2529.4 Copper as a Lewis Acid Catalyst for Asymmetric Reaction of

Imines 2559.4.1 Copper-Catalyzed Asymmetric Mannich-Type Reaction of

Imines 2559.4.2 Copper-Catalyzed Asymmetric Diels–Alder-type Reaction of Dienes

with Imines 2569.4.3 Copper-Catalyzed Asymmetric Henry Reaction of Imines 2589.5 Conclusions 259

References 260

10 Carbometallation Reactions 267Dorian Didier and Ilan Marek

10.1 Introduction 26710.2 Carbometallation of Cyclopropenes 26910.2.1 Copper-Catalyzed Carbomagnesiation 26910.2.2 Copper-Catalyzed Carbozincation 27310.3 Carbometallation of Alkynes 27410.3.1 Copper-Catalyzed Carbometallation Followed by Zinc

Homologation 27510.3.2 Copper-Catalyzed Carbomagnesiation – Elimination Sequence 27610.4 Summary 279

Acknowledgments 281References 281

11 Chiral Copper Lewis Acids in Asymmetric Transformations 283Shinya Adachi, Ramkumar Moorthy, and Mukund P. Sibi

11.1 Introduction 28311.2 Cycloadditions 28311.2.1 Diels–Alder Cycloadditions 28311.2.2 Hetero Diels–Alder Reactions 28711.2.3 [3 + 2], [2 + 2], and [4 + 3] Cycloaddition Reactions 290

X Contents

11.2.4 Nazarov Cyclization 29611.3 Claisen Rearrangements 29811.4 Ene Reactions 29911.5 Nucleophilic Addition to C=O and C=N Double Bonds 30011.5.1 Aldol Reactions 30011.5.2 Mannich-Type Reactions 30211.5.3 Nitroaldol/Nitro Mannich Reactions (Henry/Aza-Henry

Reactions) 30311.5.4 1,2-Addition-Type Friedel–Crafts Alkylation 30611.6 Conjugate Additions 30711.6.1 Mukaiyama Michael Reaction 30711.6.2 Michael Addition to Enamides 30911.6.3 Michael Addition of Carbon Nucleophiles 31011.6.4 Aza-Michael Reaction 31011.6.5 1,4-Addition-Type Friedel–Crafts Alkylation 31111.7 α-Functionalization of Carbonyl Compounds 31511.8 Kinetic Resolution 31811.9 Asymmetric Desymmetrization 31911.10 Free-Radical Reactions 32011.11 Conclusions 321

References 321

12 Mechanistic Aspects of Copper-Catalyzed Reactions 325Per-Fredrik Larsson, Per-Ola Norrby, and Simon Woodward

12.1 Introduction 32512.2 Conjugate Addition 32512.3 Allylic Alkylation and Substitution 32712.4 Copper as Lewis Acid 33312.5 1,2-Addition to Imines and Carbonyls 34012.6 Copper Hydride 34212.7 Cyclopropanation, Aziridination, and Allylic Oxidation 343

References 347

13 NMR Spectroscopic Aspects 353Felicitas von Rekowski, Carina Koch, and Ruth M. Gschwind

13.1 Introduction 35313.2 Copper Complexes with Phosphoramidite Ligands 35513.2.1 Precatalytic Copper Complexes 35513.2.1.1 Structure Determination 35513.2.1.2 Temperature Dependence 35713.2.1.3 Ligand-Specific Aggregation Trends 35913.2.2 Phosphoramidite Trialkylaluminium Interactions 36013.3 Copper Complexes with TADDOL-Based Thiolate Ligands 36113.4 Copper Complexes with Ferrocenyl-Based Ligands 36313.4.1 Structural Studies of Asymmetric Conjugate Addition Reactions 363

Contents XI

13.4.1.1 Precatalytic Copper Complexes 36313.4.1.2 Transmetallation Intermediates with Grignard Reagents 36513.4.2 Structural Studies of Asymmetric Allylic Alkylation 36813.5 Conclusion 370

Acknowledgment 371References 371

14 Applications to the Synthesis of Natural Products 373Beatriz C. Calvo, Jeffrey Buter, and Adriaan J. Minnaard

14.1 Introduction 37314.2 Copper-Catalyzed Conjugate Additions in Natural Product

Synthesis 37314.3 Natural Product Synthesis Employing Asymmetric Allylic

Alkylation 39214.4 Asymmetric Copper-Catalyzed Diels–Alder Reactions 40214.5 Asymmetric Copper-Catalyzed Mukaiyama Aldol Reactions 40614.6 Other Asymmetric Copper-Catalyzed Aldol-Type Reactions 40814.7 Asymmetric 1,3-Dipolar Cycloaddition and Claisen

Rearrangement 41014.8 Catalytic Asymmetric Cyclopropanation 41614.9 Asymmetric Copper-Catalyzed Conjugate Reductions 42214.10 Copper-Catalyzed Asymmetric 1,2-Type Addition Reactions 42614.10.1 Additions to Imines 42614.10.2 Asymmetric Copper-Catalyzed 1,2-Addition of Allyl Cyanides to

Aldehydes 42714.11 Miscellaneous Asymmetric Copper-Catalyzed Reactions 42714.11.1 Copper(I)-Catalyzed Asymmetric Desymmetrization 42714.11.2 Copper-Catalyzed Enantiospecific Ring Expansion of Oxetane 43014.11.3 Asymmetric Copper-Catalyzed Propargylic Substitution 43014.11.4 Asymmetric Proto-Boryl Additions to Vinyl Silanes 43214.11.5 Enantioselective Intramolecular Alkene Carboamination 43514.11.6 Copper-Catalyzed Asymmetric Friedel–Crafts

Alkylation/N-Hemiacetalization 43614.11.7 Atroposelective Copper-Catalyzed Oxidative Phenol Coupling 43614.12 Conclusion 438

References 441

Index 449

XIII

List of Contributors

Shinya AdachiNorth Dakota State UniversityDepartment of Chemistry andBiochemistry1231 Albrecht BoulevardFargoND 58108USA

Alexandre AlexakisUniversity of GenevaDepartment of OrganicChemistryPostfach 301211 Geneve 4Switzerland

Olivier BasleEcole Nationale Suprieure deChimie de Rennes CNRSUMR 622611 Allee deBeaulieuCS 5083735708 Rennes Cedex 7France

Jeffrey ButerStratingh Institute for ChemistryDepartment of Bio-OrganicChemistryNijenborgh 79747 AG GroningenThe Netherlands

Beatriz C. CalvoStratingh Institute for ChemistryDepartment of Bio-OrganicChemistryNijenborgh 79747 AG GroningenThe Netherlands

Andre B. CharetteUniversite de MontrealCentre in Green Chemistry andCatalysisDepartement de ChimieStation DowntownMontrealQuebecH3C 3J7Canada

XIV List of Contributors

Christophe CrevisyEcole Nationale Suprieure deChimie de Rennes CNRSUMR 622611 Allee deBeaulieuCS 5083735708 Rennes Cedex 7France

Audrey Denicourt-NowickiEcole Nationale Suprieure deChimie de Rennes CNRSUMR 622611 Allee deBeaulieuCS 5083735708 Rennes Cedex 7France

Dorian DidierTechnion-Israel Institute ofTechnologySchulich Faculty of Chemistryand the Lise Meitner-MinervaCenter for ComputationalQuantum ChemistryTechnion CityHaifa 32000Israel

Ruth M. GschwindUniversity of RegensburgInstitute of Organic ChemistryUniversitatsstrasse 3193040 RegensburgGermany

Hajime ItoHokkaido UniversityDivision of Chemical ProcessEngineeringFaculty of EnginneringSapporo 060-8628Japan

Carina KochUniversity of RegensburgInstitute of Organic ChemistryUniversitatsstrasse 3193040 RegensburgGermany

Norbert KrauseUniversity DortmundOrganic Chemistry IIOtto-Hahn-Str. 644227 DortmundGermany

and

University of GenevaDepartment of OrganicChemistryPostfach 301211 GenevaSwitzerland

Per-Fredrik LarssonAkzo Nobel FunctionalChemicals ABUddevallavagen 17Stenungsund SE-444 85Sweden

and

University of GothenburgDepartment of Chemistry andMolecular BiologyKemivagen 10SE-412 96 GothenburgSweden

List of Contributors XV

Helene LebelUniversite de MontrealCentre in Green Chemistry andCatalysisDepartement de ChimieStation DowntownMontrealQuebecH3C 3J7Canada

Hailing LiUniversity of GenevaDepartment of OrganicChemistryquai Ernest Ansermet 301211, Geneva 4,Switzerland

Bruce H. LipshutzUniversity of CaliforniaDepartment of Chemistry andBiochemistrySanta BarbaraCA 93106USA

Ilan MarekTechnion-Israel Institute ofTechnologySchulich Faculty of Chemistryand the Lise Meitner-MinervaCenter for ComputationalQuantum ChemistryTechnion CityHaifa 32000Israel

Marc MauduitEcole Nationale Suprieure deChimie de Rennes CNRSUMR 622611 Allee deBeaulieuCS 5083735708 Rennes Cedex 7France

Adriaan J. MinnaardStratingh Institute for ChemistryDepartment of Bio-OrganicChemistryNijenborgh 79747 AG GroningenThe Netherlands

Ramkumar MoorthyNorth Dakota State UniversityDepartment of Chemistry andBiochemistry1231 Albrecht BoulevardFargoND 58108USA

Per-Ola NorrbyUniversity of GothenburgDepartment of Chemistry andMolecular BiologyKemivagen 10SE-412 96 GothenburgSweden

Mauro PineschiUniversity of PisaDepartment of PharmacyVia Bonanno 3356126 PisaItaly

XVI List of Contributors

Felicitas von RekowskiUniversity of RegensburgInstitute of Organic ChemistryUniversitatsstrasse 3193040 RegensburgGermany

Marie-Noelle RoyUniversite de MontrealCentre in Green Chemistry andCatalysisDepartement de ChimieStation DowntownMontrealQuebecH3C 3J7Canada

Masaya SawamuraHokkaido UniversityDepartment of ChemistryFaculty of ScienceHokkaido PrefectureKita WardKita 8 JonishiSapporo 060-0810Japan

Mukund P. SibiNorth Dakota State UniversityDepartment of Chemistry andBiochemistry1231 Albrecht BoulevardFargoND 58108USA

Matthieu TissotUniversity of GenevaDepartment of OrganicChemistryquai Ernest Ansermet 301211, Geneva 4,Switzerland

Kiyoshi TomiokaDoshisha Women’s College ofLiberal ArtsFaculty of PharmaceuticalSciencesKodoKyotanabe 610-0395Japan

Simon WoodwardUniversity of NottinghamSchool of ChemistryUniversity ParkNottingham NG7 2RDUnited Kingdom

Ken-ichi YamadaKyoto UniversityGraduate School ofPharmaceutical SciencesYoshidaSakyoKyoto 606-8501Japan

Yasutomo YamamotoDoshisha Women’s College ofLiberal ArtsFaculty of PharmaceuticalSciencesKodoKyotanabe 610-0395Japan

1

IntroductionAlexandre Alexakis, Norbert Krause, and Simon Woodward

Copper is a metal of choice in organometallic chemistry. It is also one of the firstmetals to be extensively used in organic synthesis. Early work in the 1960s focusedon reactivity and chemoselectivity with stoichiometric organocopper and cupratereagents. Over the years, it was realized that copper, as a transition metal, couldalso be used in catalytic amounts mainly associated with Grignard reagents.

The stereoselectivity aspect has also been addressed quite early, again withstoichiometric reagents. Logically, the next step was to apply these stereoselectiveprocesses to asymmetric synthesis, thanks initially to chiral auxiliaries. Excellentmethodologies affording highly enantioenriched compounds emerged in the 1970sand 1980s. At the same time, purely enantioselective methods with chiral het-erocuprates or ligands could not bring really viable solutions, with the notableexception of cyclopropanation. It has to be emphasized that most authors focusedon the most popular reaction, that is, conjugate addition.

One of the problems in organocopper chemistry was the lack of mechanisticknowledge to better apprehend how a ligand could interact with the metal and thesubstrate. Considerable progress was made in the 1990s, particularly owing to newspectroscopic methods and density functional theory (DFT) calculations. Despitethat, the design of chiral ligands remains essentially experimental.

Enantioselective and catalytic organocopper reactions really took off in the late1990s. New ligands and new types of primary organometallics were introducedthat allowed high ee’s and high turnovers. Of course these turnovers do not matchthe levels of asymmetric hydrogenations, but they are quite good for C–C bondformation. Thus, asymmetric conjugate addition and allylic substitution afford,nowadays, excellent enantioselectivities (95–99%), both for tertiary and quaternarycenters. Further, the range of substrates is becoming larger and larger, and thenumber of available chiral ligands is over 600, as disclosed in the last decade!With the development of new methodologies, there is a boom in the applicationsto synthesis of natural products, showing the increasing interest of the chemicalsynthetic community. A cursory search of the Scifinder database reveals that thefield of enantioselective reactions promoted by copper has maintained remarkablegrowth in the period 1970–2012, with the number of publications doubling every5–8 years (Figure 1).

Copper-Catalyzed Asymmetric Synthesis, First Edition.Edited by Alexandre Alexakis, Norbert Krause, and Simon Woodward.© 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.

2 Introduction

2000

1500

1000

500

0'70−'75 '75−'80 '80−'85 '85−'90 '90−'95 '95−'00 '00−'05 '05−'12

Figure 1 Number of publications containing the keywords ‘enantioselective’ and ‘copper’ inthe Scifinder database during the period 1970–2012.

The aim of this book is to capture the essence of this activity and introducethe reader to the variety of solutions for many reaction types involving coppercatalysis. For the most popular reactions, conjugate addition and allylic substitution,a primary organometallic is needed. Therefore, a whole chapter is devoted tounderstand their subtleties and advantages and how they interact with copper salts.Asymmetric conjugate addition is a mature field and a chapter is devoted to thevariety of substrates and experimental combinations. Multiunsaturated substrates,which were introduced more recently, add one more variable to the equation, thatis, that of regioselectivity. Another chapter is devoted to allylic substitution, a trulyfascinating reaction that differs considerably from reactions catalyzed by othertransition metals (Pd, Ir, Mo, etc.). The extension of allylic substitution to othertypes of electrophiles, such as epoxides, is also described in a chapter dedicated tothis. Another recent aspect is the use of noncarbon nucleophiles, such as B andSi, and a special chapter is devoted to this aspect. Reductions with intermediatecopper hydrides have also been investigated with excellent results. Other chaptersdeal with less known reactions, such as the carbometallation, the additions toimines, and related systems. Special chapters are devoted to the older successfulcopper-catalyzed reactions, such as cyclopropanation and aziridination, and the useof copper(II) Lewis acids. In parallel to the synthetic aspects, mechanistic studiesshed new light on the processes involved–two chapters concern these aspects.Finally, it should be recalled that all the new methodologies, asymmetric or not,catalytic or stoichiometric, show their true value when applied to total synthesis.This is why a whole chapter is devoted to synthetic applications.

We hope that this book will help the readers in finding their topic of interest andthe best way to include this chemistry in their synthetic plans and applications.

3

1The Primary Organometallic in Copper-Catalyzed ReactionsSimon Woodward

1.1Scope and Introduction

In this chapter, the term primary organometallic will mean both the terminalorganometallic (RM) selected for a desired asymmetric transformation and thoseCu-species that result once the RM is combined with a suitable copper precursor.A significant advantage in copper-promoted chemistry is the ability to access a verywide library of M[CuXRLn] species (M, main group metal; X, halide or pseudohalide;R, organofunction; L, neutral ligand) by simple variation of the admixed reactioncomponents. Normally, the derived cuprate mixture is under rapid equilibriumsuch that if one species demonstrates a significant kinetic advantage, highly selectivereactions can be realized. The corollary to this position is that deconvoluting theidentity of such a single active species from the inevitable ‘‘soups’’ that resultfrom practical preparative procedures can prove highly challenging. In this review,we concentrate on asymmetric catalytic systems developed in the last 10 years,but where necessary, look at evidence from simpler supporting achiral/racemiccuprates. Our aim is to try and present a general overview of bimetallic (chiral)cuprate structure and reactivity. However, given this extremely wide remit, thecoverage herein is necessarily a selective subset from the personal perspectiveof the author. There are a number of past books of general use (either totallyor in part) that provide good primers for this area [1]. Additionally, because ofits relevance the reader is advised to also consult Chapter 12, which deals withmechanism.

Copper-Catalyzed Asymmetric Synthesis, First Edition.Edited by Alexandre Alexakis, Norbert Krause, and Simon Woodward.© 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.

4 1 The Primary Organometallic in Copper-Catalyzed Reactions

Mg

Li

Na

n = 22

n = 0

n = 0 n = 0

n = 0 n = 0 n = 0n = 6

n = 0

n = 0

Ben = 0

n = 247

K

Rb

Ca

Sr

Znn = 63

Cd

Bn = 12

Aln = 11

Ga

In

Sin = 58

Gen = 0

Sn

IA IIA IIB III IV

Partial periodic table ofasymmetric copper

processes

42%

36%

39%

92%

55%

28%

66%

Figure 1.1 Approximate relative use (n) of group II–IV organometallics in copper-promoted asymmetric processes, and percentage increase of activity over 2007–mid 2012(black roundels)1).

1.2Terminal Organometallics Sources Available

One partial representation of the totality of asymmetric processes promoted bycopper and main group organometallic mixtures is given in Figure 1.1; wherethe height of the bar indicates published activity (n = number of papers, etc.) andthe percentage in the black roundel is the fraction published in the last 5 years(2007–2012).

The seven metals identified (Li, Mg, Zn, B, Al, Si, and Sn) form the basis of thisoverview. It should be noted that (i) the dominance of magnesium is due to numer-ous simple addition reactions where the resultant stereochemistry is controlledonly by a chiral substrate; (ii) asymmetric reactions of the organometallics of thelower periods are still largely unreported; (iii) while all areas have developed, therehas been especial interest in some metalloids in recent years (e.g., organoboronreactions); and (iv) the use of silicon organometallics is over reported in Figure 1.1by the extensive use of silanes as reducing agents. The general properties of theorganometallics used in asymmetric copper-promoted reactions are given in Table1.1, compared with a generalized LCuR fragment. A common feature is their

1) The data arises from a Scifinder search (24April 2012) of the terms: ‘‘copper, asymmet-ric, and the various organoelement terms(e.g., organolithium, etc.).’’ For Mg and Si,the more common terms Grignard and silanewere used. Manual screening of the derived

dataset indicated the applicability of the ref-erences to this chapter. A similar ratio of usewas attained from substructure searching ofasymmetric reactions of RM with generalizedsubstrates.

1.3 Coordination Motifs in Asymmetric Copper Chemistry 5

Table 1.1 Properties of main group organometallics used in asymmetric Cu-promotedprocesses in order of element electronegativity.a

Organometallic M–Me bond M–C bond M–O bond Electronegativityb Oxophilicityc

type(s) energy length (A) energy(kcal mol−1) (kcal mol−1)[kJ mol−1] [kJ mol−1]

LiR 64 [267] 2.31 112 [470] 0.98 1.7RMgX, MgR2 60 [253] 2.15 113 [471] 1.31 2.3AlR3, AlRnY3−n 68 [283] 1.97 101 [418] 1.61 1.6ZnR2, RZnX 68 [285] 1.93 91 [381] 1.65

Transmetallationeasier 2.4

LCuRd 57 [238] 1.98 49 [204] 1.90

Transmetallationharder

0.7

SiR4, R1SiR23 77 [320] 1.85 100 [419] 1.90 2.0

SnR4, R1SnR23 63 [262] 2.16 49 [203] 1.96 1.0

BR3, RBY2 89 [374] 1.58 124 [519] 2.04 1.5

aMost data in Table 1 from Ref. [2], 1 kcal mol−1 is 4.19 kJ mol−1; X = halide, Y = OR.bPauling’s scale, data from Ref. [3].cE(M − O)/E(M − S) is often taken to correlate to a metal’s oxophilic HSAB character, see Ref. [2].dGeneralized data from additional citations in Ref. [2].

tendency to form strong bonds with oxygen, providing strong thermodynamicdriving forces for additions to carbonyl-containing substrates. This tendency can becorrelated to their relatively low electronegativities and high oxophilicities (‘‘hard-ness’’ defined here as E(M − O)/E(M − S)]. The published Sn–O bond energy,derived from density functional theory (DFT) calculation, is probably somewhatunderestimated in this respect. The reactivity of main group organometallics inTable 1.1 is reinforced by their weak M–C bonds. In fact, M–Me values are oftenupper limits – the bond energies of the higher homologs are frequently lower by5–10 kcal mol−1 meaning that in mixed R1MMen the methyls can be used as apotential nontransferable groups. Similarly, significant increases in the reactivityof organoelement compounds across the series M(alkyl), M(aryl), and M(allyl) areobserved. At least in the allyl case, this is correlated to the M–C bond strength,which is typically >10 kcal mol−1 lower than M–Me.

1.3Coordination Motifs in Asymmetric Copper Chemistry

Copper-promoted asymmetric reactions frequently attain high enantioselectivitythrough reduction in substrate conformational mobility via two-point binding, asin the general copper(I) cuprates 1a,b or by η2-binding at chiral CuII complexes,generalized by 2 (Scheme 1.1). As copper(II) does not form organometallic species,and readily undergoes reduction to CuI in the presence of RM, we concentrate heremainly on the former (overviews of activation by 2 can be found through the work

6 1 The Primary Organometallic in Copper-Catalyzed Reactions

O

Cu

M

R

Bridge

X

Cu

M

R

Bridge O

Cu

M

R

Bridge

RR*L *L

L*

L*

L*

O

CuD

RO

1a 1a 2 3

Scheme 1.1 Generalized binding modesfor Cu-promoted activation of prochiralsubstrates where MR is a main grouporganometallic, X is a halogen, D is a

generalized two electron donor, and ‘‘bridge’’is a generalized anionic ligand. Extension toanalogous isoelectronic fragments (e.g., NRfor O, etc.) is, of course, possible.

of Rovis and Evans [4]). One other common scenario is use of a chiral Lewis acidfragment linked to a simple heterocuprate via a bridging ligand 3.

Clearly, in attaining enantioselective transition states for asymmetric reactions,the nature of the bridging ligand (typically a halide or pseudohalide) is at least asimportant as the identification of an effective chiral ligand (L*) in attaining effectivedocking of substrates in 1–3.

1.3.1Classical Cuprate Structure and Accepted Modes of Reaction

1.3.1.1 Conjugate AdditionOwing to their initial discovery, an enormous degree of activity has focused onthe structures and reactivity of the Gillman-type homocuprates (LiCuR2) andtheir heterocuprate analogs (LiRCuX, where X is the halide of pseudohalide [5]).In general, while these systems have provided underlying understanding of thebasics of copper(I)/copper(III) organometallic chemistry they have not directlyprovided reagents that give highly selective catalytic asymmetric methodology. It isinstructive to ask, ‘‘Why is this the case?’’ – a question that modern computationalDFT understanding of the reaction course can cast light on. In classic conjugateaddition, dimeric [LiCuMe2]2 reacts with cyclohexenone via transition state 4 [6],in which the enone-bound copper is formally at the +3 oxidation state (Scheme1.2). One issue is that coordination of the d8 CuIII center with an additional neutralchiral ligand (e.g., a phosphine) has to compete with excess strong σ-ligands inthe solution (e.g., Me−), and also from intramolecular donation from the enolateπ-bond (which renders the Cu-center coordinatively saturated). Another issue isassociated with the lability of any ([R–Cu–R]Li)n bridge. Although Li–O contactsin organocuprates are essentially covalent, an ionic formulation for 4 has beenused here to emphasize the propensity of such units to exchange and associate.Such behavior is nicely demonstrated by the diffusion NMR studies of Gschwind[7], which measure the ‘‘size’’ of cuprates in solution allowing estimations oftheir identities. These studies show how easily cuprate-based bridges are readilydisplaced by tetrahydrofuran (THF) (leading to a catastrophic enone inactivation byloss of the Oenone· · ·Li Lewis acid contact) or, alternatively, promotion of multiple

1.3 Coordination Motifs in Asymmetric Copper Chemistry 7

Me Cu Me

LiLi

MeCuMe

+

O

CuO

Me Li

Me

Me

Cu

MeLi

4

III Conformationand exchangelabile bridge

Cu(III)reductive

eliminationrate limiting

Coordinativelysaturated

N

MeO

Cu R

Li Li

N

OMe

R Cu

O

5

O

R

Up to 83% ee

NPh

NMe

Cu

nPr

HA

HA

O

LiδHA −0.20, −0.30

HB

HBδHB 3.40, 3.55

I

I

I

6

I

I

Labile

Oxidativeaddition

Scheme 1.2 Transition state issues and heterocuprate solutions in early reagent-controlledasymmetric syntheses.

species through aggregation of 4 in less polar solvents. This ease of displacement

of homocuprate bridging groups by ‘‘lithium-liking’’ pseudohalides (e.g., alkoxide

impurities in RLi or derived from halides in CuX precursors) sparked, even in the

earliest days, ideas of avoiding such problems through heterocuprates LiRCuX*

use (where X* provides a rigid ordered bridge promoting strong transfer of

stereochemistry). The proposal of Dieter and Tokles 5 [8] (Scheme 1.2) is one such

case. In fact, related species have been characterized in solution by NMR, of which

6 is a nice example [9].

Chiral heterocuprates of types 5 and 6, and other species using alkoxide-based

units, or related units controlling chirality through motif 3 (e.g., the sparteine-based

reagents of Dieter [10]) have all provided rich structural chemistry [11] and effective

asymmetric stoichiometric reagents for target synthesis [8, 10]. However, such chiral

heterocuprate approaches have not transferred well to catalytic applications. Even

the most effective system of van Koten [12] (Scheme 1.3) provides only a modest 76%

eemax in the addition of MeMgI to benzylidene acetone. This is not due to a failure in

chiral recognition by the cuprate derived from 7 but due to unavoidable transfer of

the chiral thiolate donor to the terminal main group RM source, which is facilitated

by the excess of MeMgI present in the catalytic system. This provides inactive

magnesium chiral thiolates and highly debilitating racemic catalysis through small

amounts of MgBr[CuMe2]. Davies et al. [13] has demonstrated an explicit case of

the failure of a related ‘‘nontransferable’’ amido group in 8 as this undergoes rapid

exchange on the NMR timescale leading, ultimately, to a mixture of homo and

heterocuprates at 0 ◦C (Scheme 1.3).

8 1 The Primary Organometallic in Copper-Catalyzed Reactions

NMe2

S Cu

7Cu NBn2

CuBn2N

LiLi

LiCu(Mes)2

+

LiCu(NBn2)2

Stepwise50 : 50

8

O OMeMgI

9 mol % 7Et2O 0 °C

76% ee

OH

Not formed

Scheme 1.3 Exchange of hetero groups in chiral heterocuprates and effects on selectivity.

Me Cu Me

LiLi

MeCuMe

+

OAc

9

IIII

I

Oxidativeaddition Cu

O

O

Me MeLi

MeCu

Me

Li

γ

α

IIICu

Me Me

–LiCuMe2–LiOAc

10-π

IIICu

Me Me

IIICu

Me Me

10-σ1

10-σ2

IIICu

O

O

Me C

Li

Me

Cu

MeLi

N

2.02

1.99

11

Me

OAc

Me

+

Me

αγγ αMe Me

Reagent

0 °C

Strongerγ interaction

12LiCuMe2

LiCuMe(CN)50 : 5096 : 4

Scheme 1.4 DFT modeling of SN2′ allylation regiochemistry (key bond lengths in angstromnext to Cγ –Cu).

1.3 Coordination Motifs in Asymmetric Copper Chemistry 9

1.3.1.2 SN2′ Allylation ReactionsDespite early successes using chiral-leaving groups, before 1999 [14], CuL*-mediated asymmetric displacements of X (X = halide, OAc, OP(O)(OEt)2, etc.)from (E)-RCH=CHCH2X proved highly challenging. While it was clear that theselective transition state(s) were normally associated with anti γ-attack of thenucleophile on allyl electrophile, the structures were rather too reactive to beidentified. Using DFT approaches, Nakamura has put forward the most usefulpicture of the reaction coordinate (Scheme 1.4) [15]. Oxidative addition of allylacetate to Gilman’s reagent defines the enantioface of the electrophile coordinatedand through transition state 9 and delivers the symmetrical π-allyl complex 10.For clarity, the γ-carbon is emphasized (•). The symmetrical nature of 10-π and itsability to undergo classic π–σ interconversion indicates that, in substituted allylicsystems, control of regiochemical issues is likely to be at least as great a challengeas inducing high levels of asymmetric selectivity. Support for these ideas comesfrom the interaction of theory and experiment. Replacing the CuMe2

− fragmentby MeCuCN− in the DFT modeled oxidative addition reveals two factors: (i) aslower oxidative addition, but (ii) high polarization of the Cu dxz-based highestoccupied molecular orbital (HOMO) providing greater electron density trans tothe CN group. This leads to more developed Cγ –Cu bond in transition state 11,which is retained in the resulting Me(CN)CuIII (allyl) intermediate (the analog of10). Faster reductive elimination of this species is also predicted, minimizing π–σ

interconversions. The predictions nicely account for the change of regioselectivityobserved in the reactions of substrate 12 (Scheme 1.4).

1.3.2Motifs in Copper-Main Group Bimetallics and Substrate Binding

The ground-state structures of active copper reagents, especially those ‘‘loaded’’with reaction substrates, are normally too labile to be isolated. While major progresshas clearly been made through computational (DFT) approaches above, scanningcrystallographic databases2) reveals a significant number of model compounds thatprovide insight into substrate binding. For example, a handful of CuOTf complexesindicate similar binding modes for alkenes, dienes, and alkynes (all Cu–C2.05–2.22 A with C=C ∼1.4 A or C≡C ∼1.2 A), phosphines (Cu–P 2.19–2.28 A),and triflate (Cu–O 2.04–2.43 A). Particularly, structures OFANAK [16] andHIZCIC [17] provide tantalizing hints that typical bridging ligands such as triflateand acetate will produce highly ordered bimetallic structures when presented withsuitable RM (Scheme 1.5). For example, in addition to clearly showing the poorerbinding of the trisubstituted alkene, stripping out the core of OFANAK providesa key CuOTf core well predisposed to bind enones and RM. Similarly, HIZCIC

2) Search of the Cambridge Crystallographic database conducted (25 April 2012). The complexesanalyzed were CAFQUV, CEJGEE, COMMAS, FUTRIV, GEKZOL, HIZCEY, HIZCIC, JUPXUN,MIMCAN, MOHLIE, OFANAK, REXJOU, TACYAX, and VIFSEJ.

10 1 The Primary Organometallic in Copper-Catalyzed Reactions

OM

Removealkeneand dockon enoneReplace

μ–O byCu–Me

CuO

OPh3P

MeS

O

F3C

O

OFANAK

Cu

O

O PPh3

S

O

CF3

O

2.11

2.18

1.36

2.262.28

2.22

2.081.35

2.08

2.09 O

OO

O

Zn Cu

H2O

TfO

2.31

2.33

1.331.97

1.981.92

1.91

Thought Experiment

2.02

1.97

Linker

HIZCICO–Cu–O = 109.9°; O–Zn–O = 132.3°

Cu···Zn = 3.73

O

M

Thought Experiment

L*Removealkeneand dockon enone

ReplaceOAc byCu–Me

Scheme 1.5 Crystallographically characterized Cu(I) complexes as pointers to enone bind-ing. Values next to bonds are interatomic distances in angstrom.

reveals the potentially tight and ordered structure that a bridging acetate can engen-der. For clarity, the C40H58N2O4 linker in HIZCIC is not shown. No structuraldata for carboxylate bridging between CuI and boron, aluminium, or silicon werefound.

An additional range of X-ray structures are available providing insights intoM-halide–Cu(I) motifs in nonisolable catalytic intermediates (M = Li, Mg, Zn, Si).These model compounds, together with selected inter Cu–X–M atomic distancesare given in Scheme 1.6. In the case of Mg and Zn, only copper(II) models could beidentified. By taking published average binding modes for the docking of carbonyloxygen species with various main group metals [2] and a value of 2.15 A forCu–Calkene binding, then rough estimates of the optimal distance (d2) the bridgingligand which should separate the Cu· · ·M pair by for an s-trans-enone 13 (such ascyclohexenone), are attained (table in Scheme 1.6).

As can be seen, for the table within Scheme 1.6, single halogen atom bridgestypically place the key M· · ·Cu bimetallic pair a little closer than the idealizedbinding mode. It can be surmised that the success of larger bridging groups (OAc,OTf, thiophene carboxylate, etc.) in asymmetric catalysis is due to their ability toincrease the Cu/M separation into an optimal range.

In the sections that follow, we focus on information that is available in real-worldcopper-based asymmetric reagents focusing on evidence that points to the structureof the primary cuprate (or other) species involved. In looking for common features,the reactivity has been grouped by metal rather than by transformation. Again,

1.4 Asymmetric Organolithium–Copper Reagents 11

Cl

Cl

Cu

TINQUC

2.322.36

Cl–Cu–Cl = 97.3°; Cl–Li–Cl = 100.6°Cu···Li = 3.08

2.40

2.41

Ph3P

Ph3P

2.272.27 Li

O

O

1.951.95

Ph2

Ph2

Cu Br

Li(THF)3

LUTMET

Cu–Br–Li = 125.0°Cu···Li = 4.17

1.92 2.27 2.43

Ar

Ar

Cu I

Li(OEt2)2

1.90 2.45

2.69

Cu–I–Li = 95.5°Cu···Li = 3.81

CAFQUV

OO

OO

OMg

ClL

Cl3Cu2.49

2.36

Cu–Cl–Mg = 122.4°Cu···Mg = 4.26

KUZHIW

H2NNH

NH2N

CuCl

Cl3Zn 2.66

2.31

Cu–Cl–Zn = 113.1°Cu···Zn = 4.16

TIPZIBN

N

N

CuLH2O

F SiF52.03 2.04

1.37

2.44 1.69

Cu–F–Si = 159.1°Cu···Zn = 4.07

EBAVAK

I I I

IIII I

Oθ

φ

R vinyl

M M vinyl

R

M d1 (Å) θ (°) φ (°) Derived d2 (Å)

O

RCu

Md2

d1

13

Li 1.94 138 20 ~4.4

Mg 2.06 143 14 ~4.6

Al 1.92 141 12

8

~4.5

Zn 2.04 128 ~4.2

Si 1.85 142 19 ~4.4

2.15

2.15

Scheme 1.6 X-ray crystal structures of M–X–Cu model complexes (interatomic distancesin angstrom) and their relationship to an idealized Cu· · ·M bound s-trans-enone (d2 calcu-lated from J mol models).

a number of reviews, especially those concentrating on catalytic chemistry arepertinent [18].

1.4Asymmetric Organolithium–Copper Reagents

Only very recently (2011) have organolithium reagents finally yielded to ligand-promoted asymmetric catalysis. Use of TaniaPhos LA with CuBr·SMe2 allows someutterly remarkable additions of alkyl organolithiums to (E)-cinnamyl bromides14 (Scheme 1.7) with near perfect enantioselectivity [19]. This catalyst is able topromote the γ-selective allylation reaction with many desirable features: (i) ArBrexchange with nBuLi is avoided (run 3), (ii) alkyl substrates with poor steric profilesare tolerated (run 4), and (iii) even normal electrophiles for RLi (Boc groupsand esters) are tolerated (run 6). The success of this chemistry is due to the

12 1 The Primary Organometallic in Copper-Catalyzed Reactions

reaction conditions – RLi is added slowly into a very nonpolar solvent mix at lowtemperature. Under these conditions, only compound 16 is formed and this isstable to excess RLi in solution. The use of nonpolar solvent is critical. Replacementof CH2Cl2 by Et2O results in the very fragile bimetallic 17 that readily expels thechiral ligand forming achiral LiCuMe2, a process that can be followed by 31P NMRspectroscopy. This decomposition pathway means that only low enantioselectivitiesare realized (28%) in Et2O. In CH2Cl2 –hexane, the ee values realized for nBuLiaddition to 14 are largely independent of the copper source used (CuBr·SMe2,CuCl, CuI, Cu(TC); TC, 2-thiophene carboxylate), suggesting that this is a rareexample of direct reaction of a ligated organocopper reagent (17) without a ligandbridge (halide or alkyl) to Li-activated 14 (cf. Scheme 1.4). This idea is supportedby the observation that similar excellent behavior is achieved for hindered iPrand sBu additions to 14 (X = Cl) using a simple phosphoramidite ligand. Clearly,mechanistic and calculative studies are needed to address this point (Scheme 1.7).

Fe

LA

1.1 equiv LiR2

CuBr·SMe2 (5 mol%)LA (6 mol%)

–80 °C

NMe2

Ph2PPPh2

P

P

R1 X

CH2Cl2 : hexane (2 : 1)14

αγ

R1

γR2

R1 R2 Yield (%) γ : α attack

15

ee (15)(%)

Ph Mea 90 90 : 10 99Ph nBu 88 90 : 10 99

X

BrBr

4-BrPh nBu 93 82 : 18 98BrnC5H11 Et 100b 94 : 6 95BrCH2OBn nC6H13 96 85 : 15 86BrOC(=O)Ph nBu 82 100 : 0 98Br

12

345

6

P

P

Cu MeP

PCu

Me

MeLi

+ 9 equiv MeLi

in Et2O

−100 °C

II > −80 °C P

P

+ LiCuMe2< −100 °C16

aIn 2 : 1 CH2Cl2 : toluene for MeLi

I

17 LA

δP −15.3, −18.6 δP −7.5, −16.0 δP −22.3, −22.6

bConversion

Scheme 1.7 Asymmetric SN2′ allylation with organolithium species.

The same simple phosphoramidite LB has very recently allowed highly enan-tioselective desymmetrization reactions of exobicyclic alkenes (Scheme 1.8) [20].However, in this case, no NMR studies were carried out on the primary organometal-lic, but clearly at least 1 equiv of Et2O is tolerated by the catalyst structure.