N-Heterocyclic Carbenes in Late Transition Metal Catalysis

Metal-catalyzed enantioselective allylation, which involves the substitution of allylic metal intermediates with a diverse range of different nucleophiles or S(N)2'-type allylic substitution, leads to the formation of C-H, -C, -O, -N, -S, and other bonds with very high levels of asymmetric induction. The reaction may tolerate a broad range of functional groups and has been applied successfully to the synthesis of many natural products and new chiral compounds.

Metal-catalyzed enantioselective allylation in asymmetric synthesis.

2.3.5. Multi-NHCs Linked by Spacers 3568 2.4. The Ag2O Route 3570 2.4.1. Feasibility 3570 2.4.2. Complications 3571 2.4.3. Theoretical Consideration 3572 2.5. Applications 3572 2.5.1. Ag(I)-NHCs in NHC Transfer 3572 2.5.2. Ag(I)-NHCs in Catalysis 3572 2.5.3. Ag(I)-NHCs in Medicine 3572 2.5.4. Ag(I)-NHCs in Nanomaterials 3573 3. Au(I)and Au(III)-NHCs 3573 3.1. Historical Background 3573 3.2. General Synthetic Methods 3573 3.3. Formation of Au(I)and Au(III)-NHCs 3574 3.3.1. Neutral [Au(NHC)L] 3574 3.3.2. Ionic [Au(NHC)L][Anion] 3576 3.3.3. Multinuclear Au(I)-NHCs 3578 3.3.4. Other Classes of Au(I)-NHCs 3578 3.3.5. Au(III)-NHC Complexes 3579 3.4. Applications 3579 3.4.1. Au(I)and Au(III)-NHCs in Catalysis 3579 3.4.2. Au(I)-NHCs in Medicine 3580 4. Cu(I)and Cu(II)-NHCs 3581 4.1. Historical Background 3581 4.2. General Synthetic Methods 3582 4.3. Formation of Cu(I)and Cu(II)-NHCs 3583 4.3.1. Complexes Containing the Cu(NHC)2 Core 3583 4.3.2. [Cu(NHC)(Halide)] 3583 4.3.3. [Cu(NHC)(Ligand)] 3584 4.3.4. Multinuclear Cu(I)and Cu(II)-NHCs 3589 4.4. Catalysis 3591 4.4.1. Past Events 3591 4.4.2. Recent Advancements 3591 5. Photoluminescence 3592 6. Conclusions 3594 7. Abbreviations 3594 8. Acknowledgments 3595 9. References 3595

Coinage Metal−N-Heterocyclic Carbene Complexes

Departament of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, 1211 Geneve 4, Switzerland, Department of Organic Chemistry, Stockholm University, Arrhenius Laboratoriet, 106 91 Stockholm, Sweden, Organic Chemistry II, Dormund University of Technology, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany, and Departament de Quimica Fisica i Inorganica, Universitat Rovira i Virgili, C/ Marcel · li Domingo s/n, 43007 Tarragona, Spain

Enantioselective Copper-Catalyzed Conjugate Addition and Allylic Substitution Reactions

Catalytic asymmetric C-C bond-forming reactions using organometallic reagents are among the most important of organic transformations. Frequently, these transformations are key steps in the synthesis of complex biologically active molecules. The conjugate addition (CA) and allylic alkylation (AA) with organometallic compounds are especially versatile in asymmetric C-C bond-forming reactions. These transformations are complementary to the catalytic asymmetric allylic alkylation and the Michael addition, both based on soft carbon nucleophiles (Scheme 1A). For both CA and AA, the organic moiety of the organometallic reagent reacts with the sp carbon of an electron-deficient substrate, converting it to an sp carbon (Scheme 1B). In the case of CA, subsequent quenching of the enolate leads to the final product, whereas for the related AA an appropriate leaving group is expelled to form the chiral product. The organometallic compounds used most frequently for these transformations are organozinc, Grignard, organoaluminium, organolithium and cuprate reagents. Over the last three decades considerable effort has been directed toward the development of efficient catalytic systems for the asymmetric CA and AA reactions using organometallic reagents. Complexes derived from Cu salts and chiral ligands have provided the broadest scope in the catalyzed enantioselective CA and AA of organometallic reagents. Organozinc reagents have been the most successful of the organometallic reagents in this respect. Major contributions and progress in the field of asymmetric CA and AA based on organozinc reagents have been summarized in several reviews. Organomagnesium compounds were among the first organometallic compounds to be applied to synthetic organic chemistry and the use of Grignard reagents in Cu-catalyzed CA was first reported in 1941 by Kharash and Tawney. Achieving chemo-, regioand stereocontrol in both asymmetric conjugate addition (ACA) and asymmetric allylic alkylation (AAA), however, has proven to be challenging and has restricted the application of these transformations, in particular, to total synthesis. Typical selectivity issues pertain to 1,2versus 1,4-addition (Scheme 2A) and SN2versus SN2′-substitution (Scheme 2B). The challenge faced in the development of stereoselective C-C bond-forming reactions is apparent when one considers that, despite three decades of intensive research in this area, only recently has efficient Cu-catalyzed enantioselective CA of Grignard reagents been achieved. The earlier discovery of the highly enantioselective Cu-catalyzed CA of dialkylzinc reagents allowed for replacement of Grignard reagents in this asymmetric C-C bond-forming reaction. Dialkylzinc reagents offer distinct advantages over Grignard reagents in their low reactivity in noncatalyzed reactions and their high tolerance to functional groups both on the substrate and on the organozinc reagent itself. Nevertheless, there are several advantages to the use of common mono-alkylMg halide reagents, most importantly their widespread availability and the ability to transfer all of the alkyl groups of the organometallic compound. The synthetic potential of these asymmetric transformations has driven intensive research in this area, and over the past few years major breakthroughs have been realized in the enantioselective CA and AA of Grignard reagents. * Author for correspondence. E-mail: B.L.Feringa@rug.nl Chem. Rev. 2008, 108, 2824–2852 2824

Catalytic asymmetric conjugate addition and allylic alkylation with Grignard reagents.

Copper‐Catalyzed Asymmetric Allylic Alkylation

A simple choice: Ligands termed SimplePhos (L*), based on a chiral amino and flexible aryl groups on the phosphorus atom, induce high enantioselectivity in the copper-catalyzed conjugate addition and allylic substitution of dialkyl zinc and trialkyl aluminum reagents (see scheme; CuTC=copper thiophene carboxylate).

SimplePhos monodentate ligands: synthesis and application in copper-catalyzed reactions.

We describe herein the development of the first iridium-catalyzed allylic substitution using arylzinc nucleophiles. High enantioselectivities were obtained from the reactions, which used commercially available Grignard reagents as the starting materials. This methodology was also shown to be compatible with halogen/metal exchange reactions. Its synthetic potential is demonstrated by its application towards the formal synthesis of (+)-sertraline.

Enantioselective Iridium‐Catalyzed Allylic Arylation

Scope broadened: A previously developed asymmetric Cu-catalyzed allylic substitution can be applied to more substituted allylic patterns. Two classes of -disubstituted substrates, cinnamyl derivatives and aliphatic endocyclic allylic chlorides, afford excellent regio- and enantioselectivities (see schemes; L*=phosphoramidite ligand).

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β-Disubstituted Allylic Chlorides: Substrates for the Cu-Catalyzed Asymmetric SN2′ Reaction

This mini-review discusses the rapidly growing field of asymmetric copper-catalyzed chemistry. Although the allylic substitution has been less studied than the conjugate addition, recent breakthroughs have made this methodology a very valuable synthetic tool. Thus, a primary allylic halide or phosphate reacts with Grignard or diorganozinc reagents to afford the SN' product (or ?-product) in high regio- and enantioselectivities. Besides the results of the authors, we present also other, different approaches to this reaction, with emphasis on the organo-metallic and the type of chiral ligand used.

Caroline A. Falciola

Papers

Copper‐Catalyzed Asymmetric Allylic Alkylation

SimplePhos monodentate ligands: synthesis and application in copper-catalyzed reactions.

Enantioselective Iridium‐Catalyzed Allylic Arylation

β-Disubstituted Allylic Chlorides: Substrates for the Cu-Catalyzed Asymmetric SN2′ Reaction

The copper-catalyzed asymmetric allylic substitution