Modern Aldol Reactions, 2 Volume Set

Born in 1950, Rainer Mahrwald studied chemistry at MLU Halle and subsequently joined the "Manfred von Ardenne" Research Institute in Dresden, where he led the synthetics group. He gained his doctorate under G. Wagner in Leipzig in 1979, and went on to the Institute of Organic Chemistry at the Academy of Science in Berlin, where he remained until 1990. Following a stay at the Philipps-University in Marburg, Dr. Mahrwald qualified as a lecturer at the Humboldt University Berlin, where he is now a private lecturer.

• Volume 1Preface xviiList of Contributors xix1 Fundamentals and Transition-state Models. Aldol Additions of Group 1 and 2 Enolates 1Manfred Braun1.1 Introduction 11.2 The Acid or Base-mediated ‘‘Traditional’’ Aldol Reaction 21.3 The Aldol Addition of Preformed Enolates – Stereoselectivity and Transition-state Models 91.4 Stereoselective Aldol Addition of Lithium, Magnesium and Sodium Enolates 251.4.1 Addition of Chiral Enolates to Achiral Carbonyl Compounds 261.4.1.1 a-Substituted Enolates 261.4.1.2 a-Unsubstituted Enolates 321.4.2 Addition of Achiral Enolates to Chiral Carbonyl Compounds 411.4.3 Addition of Chiral Enolates to Chiral Carbonyl Compounds 491.4.4 Addition of Achiral Enolates to Achiral Carbonyl Compounds in the Presence of Chiral Additives and Catalysts 511.5 Conclusion 52References 532 The Development of Titanium Enolate-based Aldol Reactions 63Arun K. Ghosh, M. Shevlin2.1 Introduction 632.2 Additions of Enolates to Ketones 652.3 Addition of Enolates Without α-Substituents to Aldehydes 662.3.1 Stereoselective Acetate Aldol Reactions Using Chiral Auxiliaries 672.3.2 Stereoselective Acetate Aldol Reactions Involving Chiral Titanium Ligands 692.3.3 Alternative Approaches to Acetate Aldol Adducts 702.4 Addition of Enolates with α-Substituents to Aldehydes 722.4.1 Syn Diastereoselectivity 742.4.1.1 Synthesis of syn Aldols in Racemic Form 752.4.1.1.1 Reactions of Ketones 752.4.1.1.2 Reactions of Esters and Thiol Esters 772.4.1.1.3 Aldol Reactions of Aldehyde Hydrazones 782.4.1.2 Synthesis of Optically Active syn Aldols Using Chiral Auxiliaries 802.4.1.2.1 Amino Acid-derived Oxazolidinone and Related Auxiliaries 802.4.1.2.2 Camphor-derived Chiral Auxiliaries 842.4.1.2.3 Aminoindanol and Amino Acid-derived Chiral Auxiliaries 872.4.1.2.4 Other Chiral Auxiliaries 902.4.1.3 Synthesis of Optically Active syn Aldols Using Chiral Titanium Ligands 922.4.1.4 Synthesis of Optically Active syn Aldols with Chiral Enolates 952.4.2 Anti Diastereoselectivity 982.4.2.1 Synthesis of anti Aldols in Racemic Form 982.4.2.2 Synthesis of Optically Active anti Aldols by Use of Chiral Auxiliaries 992.4.2.2.1 Aminoindanol and Related Chiral Auxiliaries 992.4.2.2.2 Oxazolidinethione and Oxazolidineselone Chiral Auxiliaries 1032.4.2.3 Synthesis of Optically Active anti Aldols by Use of Chiral Titanium Ligands 1042.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions 1052.5.1 Lactone Natural Products 1052.5.1.1 Tetrahydrolipstatin 1062.5.1.2 Myxopyronins A and B 1062.5.1.3 Callystatin A 1072.5.1.4 Ai-77-B 1082.5.2 Macrolide Natural Products 1102.5.2.1 Epothilone 490 1102.5.2.2 Cryptophycin B 1102.5.2.3 Amphidinolide T1 1112.5.2.4 Rapamycin 1122.5.2.5 Spongistatins 1 and 2 1132.5.3 Miscellaneous Natural Products 1142.5.3.1 Tautomycin 1142.5.3.2 Crocacin C 1152.5.3.3 Stigmatellin A 1162.5.3.4 Denticulatin B 1172.5.3.5 Membrenone C 1192.6 Typical Experimental Procedures for Generation of Titanium Enolates 1202.6.1 Experimental Procedures 1202.6.2 Alternative Approaches to Titanium Enolate Generation 1212.7 Conclusion 121References 1223 Boron and Silicon Enolates in Crossed Aldol Reaction 127Teruaki Mukaiyama and Jun-ichi Matsuo3.1 Introduction 1273.2 Crossed Aldol Reactions Using Boron Enolates 1273.2.1 Discovery of Aldol Reaction Mediated by Boron Enolates 1273.2.2 New Method for Direct Generation of Boron Enolates 1293.2.3 Regioselectivity on Generation of Boron Enolates 1303.2.4 Stereoselective Formation of (E) or (Z) Boron Enolates 1313.2.5 syn-Selective Asymmetric Boron Aldol Reactions 1343.2.6 anti-Selective Asymmetric Aldol Reaction 1353.3 Crossed Aldol Reactions Using Silicon Enolates 1373.3.1 Discovery of Silicon Enolate-mediated Crossed Aldol Reactions 1373.3.2 Lewis Acid-catalyzed Aldol Reactions of Silicon Enolates 1433.3.3 Non-catalyzed Aldol Reactions of Silicon Enolates 1473.3.4 Lewis Base-catalyzed Aldol Reactions of Trimethylsilyl Enolates 1483.3.5 Diastereoselective Synthesis of Polyoxygenated Compounds 1493.3.6 Asymmetric Aldol Reactions Using Chiral Tin(II) Lewis Acid Catalysts 1503.3.6.1 Stoichiometric Enantioselective Aldol Reaction 1513.3.6.2 Catalytic Enantioselective Aldol Reaction 154References 1554 Amine-catalyzed Aldol Reactions 161Benjamin List4.1 Introduction 1614.2 Aminocatalysis of the Aldol Reaction 1624.2.1 Intermolecular Aldolizations 1634.2.1.1 Aldehyde Donors 1644.2.1.2 Ketone Donors 1664.2.2 Intramolecular Aldolizations 1674.2.2.1 Enolexo Aldolizations 1674.2.2.2 Enolendo Aldolizations 1714.3 Asymmetric Aminocatalysis of the Aldol Reaction 1734.3.1 Intramolecular Aldolizations 1734.3.1.1 Enolendo Aldolizations 1734.3.1.2 Enolexo Aldolizations 1774.3.2 Intermolecular Aldolizations 1794.3.2.1 Ketone Donors 1794.3.2.2 Aldehyde Donors 193References 1965 Enzyme-catalyzed Aldol Additions 201Wolf-Dieter Fessner5.1 Introduction 2015.2 General Aspects 2025.2.1 Classification of Lyases 2025.2.2 Enzyme Structure and Mechanism 2045.2.3 Practical Considerations 2075.3 Pyruvate Aldolases 2085.3.1 N-Acetylneuraminic Acid Aldolase 2085.3.2 KDO Aldolase 2165.3.3 DAHP Synthase 2175.3.4 KDPG Aldolase and Related Enzymes 2185.4 Dihydroxyacetone Phosphate Aldolases 2215.4.1 FruA 2225.4.2 TagA 2245.4.3 RhuA and FucA 2245.4.4 DHAP Synthesis 2275.4.5 Applications 2305.4.6 Aldol Transfer Enzymes 2465.5 Transketolase and Related Enzymes 2475.6 2-Deoxy-D-ribose 5-Phosphate Aldolase 2505.7 Glycine Aldolases 2545.8 Recent Developments 2575.9 Summary and Conclusion 258References 2606 Antibody-catalyzed Aldol Reactions 273Fujie Tanaka and Carlos F. Barbas, III6.1 Introduction 2736.2 Generation of Aldolase Antibodies 2736.2.1 Antibody as Catalyst Scaffold 2736.2.2 Generation of Aldolase Antibodies that Operate via an Enamine Mechanism 2746.2.2.1 Reactive Immunization with the Simple Diketone Derivative 2756.2.2.2 Combining Reactive Immunization with Transition-state Analogs 2776.2.2.3 Reactive Immunization with other Diketones 2796.3 Aldolase Antibody-catalyzed Aldol and Retro-aldol Reactions 2796.3.1 Antibody 38C2-catalyzed Aldol Reactions 2806.3.2 Antibody 38C2-Catalyzed Retro-aldol Reactions and their Application to Kinetic Resolution 2836.3.3 Aldol and Retro-aldol Reactions Catalyzed by Antibodies 93F3 and 84G3 2856.3.4 Preparative-scale Kinetic Resolution Using Aldolase Antibodies in a Biphasic Aqueous–Organic Solvent System 2886.3.5 Aldolase Antibody-catalyzed Reactions in Natural Product Synthesis 2906.3.6 Retro-aldol Reactions in Human Therapy: Prodrug Activation by Aldolase Antibody 2916.4 Aldolase Antibodies for Reactions Related to an Enamine Mechanism and the Nucleophilic Lysine ε-Amino Group 2936.5 Concise Catalytic Assays for Aldolase Antibody-catalyzed Reactions 2976.6 Structures of Aldolase Antibodies and Reaction Mechanism of Nucleophilic Lysine ε-Amino Group 2986.7 Evolution of Aldolase Antibodies In Vitro 3026.8 Cofactor-mediated Antibody-catalyzed Aldol and/or Retro-aldol Reactions 3056.9 Summary and Conclusion 3056.10 Experimental Procedures 306Acknowledgments 307References 3077 The Aldol Reaction in Natural Product Synthesis: The Epothilone Story 311Dieter Schinzer7.1 History of Epothilones: Biological Source, Isolation, and Structural Elucidation 3117.2 History of Epothilones: The Total Synthesis Race 3117.2.1 Different Strategies with Aldol Reactions: The Danishefsky Synthesis of Epothilone A Relying on Intramolecular Aldol Reaction 3127.2.2 Different Strategies with Aldol Reactions: The Nicolaou Synthesis of Epothilone A Using an Unselective Aldol Reaction 3137.2.3 Different Strategies with Aldol Reactions: The Schinzer Synthesis of Epothilone A with Complete Stereocontrol in the Aldol Reaction 3147.3 Model Study via Chelation Control in the Aldol Reaction by Kalesse 3197.3.1 Different Aldol Strategies: Mulzer’s Total Syntheses of Epothilones B and D 3207.4 Long-range Structural Effects on the Stereochemistry of Aldol Reactions 3227.5 Summary and Conclusion 326References 326Index 329Volume 2Preface xviiList of Contributors xix1 Silver, Gold, and Palladium Lewis Acids 1Akira Yanagisawa1.1 Introduction 11.2 Mukaiyama Aldol Reaction and Related Reactions 11.3 Asymmetric Aldol Reactions of a-Isocyanocarboxylates 81.4 Summary and Conclusions 151.5 Experimental Procedures 18References 212 Boron and Silicon Lewis Acids for Mukaiyama Aldol Reactions 25Kazuaki Ishihara and Hisashi Yamamoto2.1 Achiral Boron Lewis Acids 252.1.1 Introduction 252.1.2 BF3 ⋅ Et2O 262.1.3 B(C6F5)3 292.1.4 Ar2BOH 302.2 Chiral Boron Lewis Acids 332.2.1 Introduction 332.2.2 Chiral Boron Lewis Acids as Stoichiometric Reagents 332.2.3 Chiral Boron Lewis Acids as Catalytic Reagents 402.3 Silicon Lewis Acids 532.3.1 Introduction 532.3.2 Lewis Acidity of Silicon Derivatives 542.3.3 Silicon Lewis Acids as Catalytic Reagents 552.3.4 Activation of Silicon Lewis Acids by Combination with Other Lewis Acids 60References 653 Copper Lewis Acids 69Jeffrey S. Johnson and David A. Nicewicz3.1 Introduction 693.2 Early Examples 693.3 Mukaiyama Aldol Reactions with Cu(II) Complexes 703.3.1 Enolsilane Additions to (Benzyloxy)acetaldehyde 703.3.1.1 Scope and Application 703.3.1.2 Mechanism and Stereochemistry 753.3.2 Enolsilane Additions to α-Keto Esters 803.3.2.1 Scope and Application 803.3.2.2 Mechanism and Stereochemistry 853.3.3 Enolsilane Additions to Unfunctionalized Aldehydes 883.4 Additions Involving In-Situ Enolate Formation 903.4.1 Pyruvate Ester Dimerization 903.4.2 Addition of Nitromethane to α-Keto Esters 913.4.3 Malonic Acid Half Thioester Additions to Aldehydes 943.4.4 Dienolate Additions to Aldehydes 963.4.4.1 Scope and Application 963.4.4.2 Mechanistic Considerations 973.4.5 Enantioselective Cu(II) Enolate-Catalyzed Vinylogous Aldol Reactions 993.5 Conclusions 101References 1024 Tin-promoted Aldol Reactions and their Application to Total Syntheses of Natural Products 105Isamu Shiina4.1 Introduction 1054.2 Tin-promoted Intermolecular Aldol Reactions 1054.2.1 Achiral Aldol Reactions 1054.2.2 The Reaction of Silyl Enolates with Aldehydes or Ketones 1084.2.3 The Reaction of Silyl Enolates with Acetals 1174.2.4 Reaction of Dienol Silyl Ethers 1204.3 Tin-promoted Intramolecular Aldol Reactions 1214.3.1 The Intramolecular Aldol Reaction of Silyl Enolates 1214.3.2 Reaction of Dienol Silyl Ethers or γ-Silyl-α,β-enones 1234.4 Chiral Diamine–Sn(II) Complex-promoted Aldol Reactions 1244.4.1 Asymmetric Aldol and Related Reactions of Sn(II) Enolates 1254.4.2 Chiral Diamine–Sn(II) Complex-promoted Aldol Reactions 1284.4.3 Asymmetric Aldol Reaction of Silyl Enolates 1294.4.4 Catalytic Asymmetric Aldol Reaction 1314.4.5 Asymmetric Synthesis of syn- and anti-1,2-Diol Groups 1354.4.6 Enantioselective Synthesis of Both Enantiomers of Aldols Using Similar Diamines Derived from L-Proline 1394.5 Asymmetric Total Syntheses of Complex Molecules Using Chiral Diamine–Sn(II) Catalysts 1404.5.1 Monosaccharides 1404.5.2 Leinamycin and a Part of Rapamycin 1424.5.3 Sphingosine, Sphingofungins, and Khafrefungin 1454.5.4 Febrifugine and Isofebrifugine 1474.5.5 Altohyrtin C (Spongistatin 2) and Phorboxazole B 1484.5.6 Paclitaxel (Taxol) 1494.5.7 Cephalosporolide d 1534.5.8 Buergerinin F 1534.5.9 Octalactins A and B 1544.5.10 Oudemansin-antibiotic Analog 1554.6 Conclusions 1574.7 Experimental 158References 1595 Zirconium Alkoxides as Lewis Acids 167Yasuhiro Yamashita and Shū Kobayashi5.1 Introduction 1675.2 The Asymmetric Mukaiyama Aldol Reaction 1695.3 Asymmetric Hetero Diels–Alder Reaction 1755.4 Reaction Mechanism 1805.5 Structure of the Chiral Zirconium Catalyst 1845.6 Air-stable and Storable Chiral Zirconium Catalyst 1875.7 Conclusion 1905.8 Experimental 191References 1926 Direct Catalytic Asymmetric Aldol Reaction Using Chiral Metal Complexes 197Masakatsu Shibasaki, Shigeki Matsunaga, and Naoya Kumagai6.1 Introduction 1976.2 Direct Aldol Reactions with Methyl Ketones 1986.3 Direct Aldol Reactions with Methylene Ketones 2086.4 Direct Aldol Reaction with α-Hydroxyketones 2106.5 Direct Aldol Reaction with Glycine Schiff Bases 2196.6 Other Examples 2216.7 Conclusion 2246.8 Experimental Section 225References and Notes 2267 Catalytic Enantioselective Aldol Additions with Chiral Lewis Bases 229Scott E. Denmark and Shinji Fujimori7.1 Introduction 2297.1.1 Enantioselective Aldol Additions 2297.1.1.1 Background 2307.1.2 Lewis Base Catalysis 2337.1.3 Organization of this Chapter 2357.2 Preparation of Enoxytrichlorosilanes 2367.2.1 General Considerations 2387.2.2 Preparation of Ketone-derived Trichlorosilyl Enolates 2407.2.3 Preparation of Aldehyde-derived Trichlorosilyl Enolates 2467.2.4 Preparation of Trichlorosilyl Ketene Acetals 2487.3 Preparation of Chiral Lewis Bases 2497.3.1 Preparation of Chiral Phosphoramides 2507.3.2 Synthesis of Chiral bis-N-Oxides 2517.4 Enantioselective Aldol Addition of Achiral Enoxytrichlorosilanes 2537.4.1 Aldol Additions of Achiral Methyl Ketone-derived Enolates 2547.4.2 Aldol Additions of Cyclic Trichlorosilyl Enolates 2637.4.3 Addition of Acyclic Ethyl Ketone-derived Enolates 2677.5 Diastereoselective Additions of Chiral Enoxytrichlorosilanes 2727.5.1 Aldol Addition of Lactate-derived Enoxytrichlorosilanes 2737.5.1.1 Methyl Ketone-derived Enolates 2737.5.1.2 Ethyl Ketone-derived Enolates 2777.5.2 Aldol Addition of β-Hydroxy-α-Methyl Ketone-derived Enoxytrichlorosilanes 2807.5.2.1 Methyl Ketone-derived Enolates 2807.5.2.2 Ethyl Ketone-derived Enolates 2827.5.3 Addition of Enoxytrichlorosilanes with a β-Stereogenic Center 2837.6 Aldol Additions of Aldehyde-derived Enoxytrichlorosilanes 2887.7 Aldol Addition of Trichlorosilyl Ketene Acetal to Aldehydes and Ketones 2947.8 Lewis Base Activation of Lewis Acids – Aldol Additions of Silyl Enol Ethers to Aldehydes 2987.9 Toward a Unified Mechanistic Scheme 3057.9.1 Cationic Silicon Species and the Dual-pathway Hypothesis 3067.9.2 Unified Mechanistic Scheme 3107.9.3 Structural Insights and Modifications 3127.10 Conclusions and Outlook 3157.11 Representative Procedures 3167.11.1 Preparation of Enoxytrichlorosilanes 3167.11.2 Aldol Addition of Ketone-derived Enoxytrichlorosilane 317References 3198 The Aldol–Tishchenko Reaction 327R. Mahrwald8.1 Introduction 3278.2 The Aldol–Tishchenko Reaction 3278.2.1 The Aldol–Tishchenko Reaction with Enolizable Aldehydes 3278.2.2 The Aldol–Tishchenko Reaction with Ketones and Aldehydes 3298.2.3 The Evans–Tishchenko Reduction 3348.2.4 Related Reactions 3398.3 Representative Procedures 341References 342Index 345

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