Chapter 1
The Catalytic, Enantioselective Michael Reaction

Efraím Reyes, Uxue Uria, Jose L. Vicario*, and Luisa Carrillo

Department of Organic Chemistry II, Faculty of Science and Technology, University of the Basque Country, UPV/EHU. P.O. Box 644, E-48080, Bilbao, Spain

1. Acknowledgments
2. Introduction
3. Mechanism and Stereochemistry
   1. Metal-Catalyzed Reactions
      1. Metal-Catalyzed Direct Michael Reaction
      2. Metal-Catalyzed Mukaiyama-Michael Reaction
   2. Organocatalyzed Reactions
      1. Enamine Activation
      2. Iminium Activation
      3. H-Bonding Activation
      4. Phase-Transfer Catalysis (PTC)
      5. Chiral Brønsted Base Catalysis
4. Scope and Limitations
   1. Metal-Catalyzed Michael Reactions
      1. Metal-Catalyzed Direct Michael Reaction
         1. Monometallic Complexes
         2. Polymetallic Complexes
      2. Metal-Catalyzed Mukaiyama-Michael Reaction
   2. Organocatalyzed Michael Reactions
      1. Enamine Activation
      2. Iminium Ion Activation
      3. Hydrogen-Bonding Catalysis
      4. Phase-Transfer Catalysis (PTC)
      5. Brønsted Base Catalysis
   3. General Overview
5. Applications to Synthesis
   1. Quinine and Quinidine (Al/Salen Metal Catalysis)225
   2. Strychnine (La/Al Binuclear Metal Catalysis)226
   3. (-)-Bitungolide F (Enamine Catalysis)227
   4. Warfarin (Iminium Catalysis)172
   5. Spiculisporic Acid (Mukaiyama-Michael Reaction under Iminium Catalysis)169
   6. (-)-Nakadomarin A (H-Bonding Catalysis)228 229
   7. Baclofen (Phase-Transfer Catalysis)208
   8. NP25302 (Brønsted Base Catalysis)230
6. Comparison with Other Methods
7. Experimental Conditions
   1. 1. Metal-Catalyzed Direct Michael Reaction
      2. Metal-Catalyzed Mukaiyama-Michael Reaction
      3. Michael Reaction under Enamine Activation
      4. Michael Reaction under Iminium Activation
      5. Michael Reaction under H-bonding Activation
      6. Michael Reaction under Phase-Transfer Catalysis
8. Experimental Procedures
   1. Preparation of Selected Ligands and Catalysts
      1. (3aS,7S)-3,3-Diphenyl-1-(p-tolyl)hexahydro-1H-pyrrolo[1,2-c][1,3,2]oxazaborol-7-ium Triflamide [Preparation of Corey's Oxazaborolidine Catalyst].56
      2. LSB Complex [Preparation of Shibasaki's Binuclear Lanthanide/Alkaline Metal/BINOL Catalyst].50
      3. (4S,4´S)-2,2´-(Propane-2,2-diyl)-bis(4-tert-butyl-4,5-dihydrooxazole)copper (II) Chloride · CH2Cl2 [Preparation of the Cu(II)/(S,S)-t-Bu-box Complex].55
      4. (S)-2-[Diphenyl(trimethylsilyloxy)methyl]pyrrolidine (O-TMS Diphenylprolinol) [Preparation of the Jørgensen-Hayashi Catalyst].247
      5. 1-[3,5-bis(Trifluoromethyl)phenyl]-3-[(1R,2R)-2-(dimethylamino)cyclohexyl]thiourea [Preparation of Takemoto's Thiourea].86
      6. O-Allyl-N-(9-anthracenylmethyl)cinchonidium Bromide [Preparation of Corey's Cinchona-Based Ammonium Salt].248
   2. Selected Experimental Procedures for Catalytic Enantioselective Michael Reactions
      1. (S)-(-)-2-Methyl-2-(3-oxocyclohexyl)propionic Acid, Methyl Ester [Oxazaborolidine-Catalyzed Mukaiyama-Michael Reaction].56
      2. (2S,3S)-2,3-Dimethyl-5-[2-oxo(1,3-oxazolidin-3-yl)]-1-pyrrolylpentane-1,5-dione [Cu(II)/Box-Catalyzed Mukaiyama-Michael Reaction].55
      3. (S)-4-Nitro-1,3-diphenylbutan-1-one. [Sc(III)/N,N-Dioxide Complex Catalyzed Michael Reaction].105
      4. (S)-Methyl 3,5-Diphenyl-2-methoxycarbonyl-5-oxopentanoate. [La/Na-BINOL Heterodinuclear Complex Catalyzed Michael Reaction].50
      5. (2R,3S)-2-Methyl-4-nitro-3-phenylbutanal [O-TMS-Diphenylprolinol-Catalyzed Michael Reaction under Enamine Activation].60
      6. (S)-4-Nitro-3-phenylbutanal [O-TMS-Diphenylprolinol-Catalyzed Michael Reaction under Iminium Activation].153
      7. (S)-Ethyl 2-Carboethoxy-4-nitro-3-phenylbutyrate [Takemoto's Thiourea-Catalyzed Michael Reaction].86
      8. (S)-1-(tert-Butyl) 5-Methyl 2-(Diphenylmethyleneamino)pentanedioate [Cinchonidinium Salt Catalyzed Michael Reaction].206
9. Tabular Survey
   1. Chart 1. Catalysts and Ligands Used in the Tables
   2. Table 1. Ketones, Silyl Enol Ethers, and Enamines as Donors
      1. A. Nitroalkenes as Acceptors
      2. B. Enones as Acceptors
      3. C. a, ß-Unsaturated Aldehydes as Acceptors
      4. D. a, ß-Unsaturated Carboxylic Acids and Related Compounds as Acceptors
      5. E. Vinylogous Michael Reactions
   3. Table 2. Aldehydes as Donors
      1. A. Nitroalkenes as Acceptors
      2. B. Enones as Acceptors
      3. C. a, ß-Unsaturated Aldehydes as Acceptors
      4. D. a, ß-Unsaturated Carboxylic Acids and Related Compounds as Acceptors
   4. Table 3. 1,3-Dicarbonyl and Related Compounds as Donors
      1. A. Nitroalkenes as Acceptors
      2. B. Enones as Acceptors
      3. C. a, ß-Unsaturated Aldehydes as Acceptors
      4. D. a, ß-Unsaturated Carboxylic Acids and Related Compounds as Acceptors
      5. E. Vinylogous Michael Reactions
   5. Table 4. Nitroalkanes as Donors
      1. A. Nitroalkenes as Acceptors
      2. B. Enones as Acceptors
      3. C. a, ß-Unsaturated Aldehydes as Acceptors
      4. D. a, ß-Unsaturated Carboxylic Acids and Related Compounds as Acceptors
   6. Table 5. Carboxylic Acids and Related Compounds as Donors
      1. A. Nitroalkenes as Acceptors
      2. B. Enones as Acceptors
      3. C. a, ß-Unsaturated Aldehydes as Acceptors
      4. D. a, ß-Unsaturated Carboxylic Acids and Related Compounds as Acceptors
      5. E. Vinylogous Michael Reactions
10. References
11. Supplemental References for Table 1A
12. Supplemental References for Table 1B
13. Supplemental References for Table 1C
14. Supplemental References for Table 1D
15. Supplemental References for Table 2A
16. Supplemental References for Table 2B
17. Supplemental References for Table 2D
18. Supplemental References for Table 3A
19. Supplemental References for Table 3B
20. Supplemental References for Table 3C
21. Supplemental References for Table 3D
22. Supplemental References for Table 3E
23. Supplemental References for Table 4A
24. Supplemental References for Table 4B
25. Supplemental References for Table 4C
26. Supplemental References for Table 4D
27. Supplemental References for Table 5A
28. Supplemental References for Table 5B
29. Supplemental References for Table 5C
30. Supplemental References for Table 5D
31. Supplemental References for Table 5E

Acknowledgments

The authors thank the Spanish MINECO (FEDER-CTQ2014-52107-P), the Basque Government (IT328-10) and UPV/EHU (UFI QOSYC 11/22) for financial support.

Introduction

The conjugate addition reaction is a fundamental transformation in synthetic organic chemistry for the construction of carbon-carbon and carbon-heteroatom bonds. This reaction consists of the addition of a nucleophile to the ß-carbon of an electrophilic olefin, leading to the formation of a stabilized anion, which after protonation or subsequent treatment with another electrophile, furnishes the final addition product. The conjugate addition of resonance-stabilized carbanions (an enolate or related species), also known as the Michael reaction, has received great attention among synthetic chemists as a general tool for the preparation of 1,5-dicarbonyl compounds. Since the first example was reported in 1887 by Arthur Michael,1 this transformation has demonstrated extraordinary generality. A wide range of compounds is able to participate in the reaction as nucleophiles or electrophiles (also referred to as Michael donors and Michael acceptors, respectively), which has expanded the usefulness of this transformation to a high level of sophistication.

The overall process of the Michael reaction can be defined in terms of three different steps (Scheme 1): (1) the activation of the pronucleophile takes place, generating an enolate or a related nucleophilic species such as a silyl enol ether or an enamine; (2) the conjugate addition reaction itself occurs; and (3) the reaction ends with the addition of a second electrophile (a proton is the most commonly encountered...