Edited by

Rainer Mahrwald

Modern Methods in Stereoselective AldolReactions

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Edited by Rainer Mahrwald

Modern Methods in Stereoselective AldolReactions

The Editor

Prof. Dr. Rainer MahrwaldHumboldt-Universitat BerlinInstitut fur ChemieBrook-Taylor-Str. 212489 Berlin

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V

Contents

Preface XIList of Contributors XIII

1 Stereoselective Acetate Aldol Reactions 1Pedro Romea and Felix Urpı

1.1 Introduction 11.2 Mukaiyama Aldol Reaction 21.2.1 Concept and Mechanism 21.2.2 Chiral Auxiliaries 41.2.3 Chiral Methyl Ketones 61.2.4 Chiral Aldehydes 81.2.4.1 1,2-Asymmetric Induction 81.2.4.2 1,3-Asymmetric Induction 131.2.4.3 Merged 1,2- and 1,3-Asymmetric Induction 171.2.5 Chiral Lewis Acids 221.2.6 Chiral Lewis Bases 351.3 Metal Enolates 411.3.1 Concept and Mechanism 411.3.2 Chiral Auxiliaries 421.3.3 Stoichiometric Lewis Acids 471.3.4 Catalytic Lewis Acids 481.3.5 Chiral Aldehydes 501.3.6 Chiral Methyl Ketones 551.3.6.1 α-Methyl Ketones 561.3.6.2 α-Hydroxy Ketones 571.3.6.3 β-Hydroxy Ketones 601.3.6.4 β-Hydroxy α-Methyl Ketones 631.3.6.5 α,β-Dihydroxy Ketones 641.3.6.6 Remote Stereocontrol 671.4 Conclusions 68

References 69

VI Contents

2 The Vinylogous Mukaiyama Aldol Reaction in Natural ProductSynthesis 83Martin Cordes and Markus Kalesse

2.1 Introduction 832.2 Aldehyde-Derived Silyl Dienol Ethers 842.2.1 Aldehyde-Derived Silyl Dienol Ethers – Diastereoselective

Processes 842.2.2 Aldehyde-Derived Silyl Dienol Ethers – Enantioselective Processes 872.3 Ester-Derived Silyl Dienol Ethers 902.3.1 Ester-Derived Silyl Dienol Ethers – Diastereoselective Processes 902.3.2 Ester-Derived Silyl Dienol Ethers – Enantioselective Processes 962.3.3 Ester-Derived Silyl Dienol Ethers – Enantioselective and

Substrate-Controlled Processes 1052.4 Amide-Derived Silyl Dienol Ethers – Vinylketene Silyl N,O-Acetals 1082.4.1 Model Systems – Kobayashi’s Pioneering Studies 1082.4.2 Total Syntheses 1092.5 Acyclic Acetoacetate-Derived Silyl Dienolates – Chan’s Diene 1172.5.1 Chan’s Diene in Diastereoselective Processes 1172.5.2 Chan’s Diene in Enantioselective Processes 1212.5.3 Chan’s Diene in Enantioselective and Substrate-Controlled

Processes 1222.6 Cyclic Acetoacetate-Derived Dienolates 1242.6.1 Cyclic Acetoacetate-Derived Dienolates – Diastereoselective

Processes 1242.6.2 Cyclic Acetoacetate-Derived Dienolates – Enantioselective

Processes 1262.6.3 Cyclic Acetoacetate-Derived Dienolates – Enantioselective and

Substrate-Controlled Processes 1322.7 Furan-Derived Silyloxy Dienes 1332.7.1 Furan-Derived Silyloxy Dienes – Diastereoselective Processes 1332.7.2 Furan-Derived Silyloxy Dienes – Enantioselective Processes 1382.7.3 Furan-Derived Silyloxy Dienes – Enantioselective and

Substrate-Controlled Processes 1412.8 Pyrrole-Based 2-Silyloxy Dienes 1422.9 Comparison with Other Methods 148

References 151

3 Organocatalyzed Aldol Reactions 155Gabriela Guillena

3.1 Introduction 1553.2 Proline as Organocatalyst 1563.2.1 Intramolecular Reactions 1563.2.1.1 Intramolecular Proposed Mechanism 1593.2.1.2 Application to Natural Product Synthesis 1613.2.2 Intermolecular Reactions 163

Contents VII

3.2.2.1 Ketones as Source of Nucleophile 1633.2.2.2 Aldehydes as Source of Nucleophile 1713.2.2.3 Intermolecular Reaction Mechanism 1753.2.2.4 Application to Natural Product Synthesis 1773.3 Proline Derivatives as Organocatalysts 1793.3.1 Prolinamide Derivatives 1803.3.1.1 Ketones as Source of Nucleophile 1803.3.1.2 Aldehydes as Source of Nucleophile 1973.3.1.3 Application to Natural Product Synthesis 1973.3.2 Proline Peptide Derivatives 1993.3.2.1 Ketones as Source of Nucleophile 1993.3.3 Hydroxyproline Derivatives 2053.3.3.1 Intramolecular Reactions 2053.3.3.2 Intermolecular Reactions 2073.3.4 Sulfonimide Proline Derivatives 2163.3.4.1 Ketones as Source of Nucleophile 2163.3.4.2 Application to Natural Product Synthesis 2193.3.5 Other Proline Derivatives 2203.3.5.1 Intramolecular Reactions 2203.3.5.2 Intermolecular Reactions 2213.3.5.3 Application to Natural Product Synthesis 2313.3.6 Other Organocatalysts 2333.3.6.1 Intramolecular Reactions 2333.3.6.2 Intermolecular Reactions 2353.3.7 Phase-Transfer Catalysis 2513.4 Conclusions and Outlook 253

References 253

4 Supersilyl Protective Groups in Aldol Reactions 269Patrick B. Brady and Hisashi Yamamoto

4.1 Introduction 2694.2 Aldol Addition with Acetaldehyde-Derived Super Silyl Enol

Ether (1) 2704.3 α-Substituted Silyl Enol Ethers Derived from Aldehydes 2704.4 Aldol Addition to Chiral Aldehydes 2724.5 One-Pot Sequential Aldol Reactions 2744.6 Sequential Aldol–Aldol Reactions of Acetaldehyde 2754.6.1 Acetaldehyde Double Aldol Reactions 2754.6.2 Acetaldehyde Triple Aldol Reactions 2754.6.3 Mixed Sequential Aldol–Aldol Reactions 2774.7 Double Aldol Reactions with α-Substituted Silyl Enol Ethers 2774.7.1 Sequential Aldol–Aldol Reactions with Mixed SEEs 2774.7.2 Propionaldehyde Aldol–Aldol Cascade Reactions 2794.7.3 Haloacetaldehyde Aldol–Aldol Cascades 2804.8 Stereochemical Considerations 281

VIII Contents

4.9 Aldol Reactions of β-Supersiloxy Methyl Ketones 2824.10 Total Synthesis of Natural Products Using Supersilyl Aldol

Reactions 2854.11 Conclusion and Outlook 288

References 288

5 Asymmetric Induction in Aldol Additions 293Luiz C. Dias, Ellen C. Polo, Emılio C. de Lucca Jr, and Marco A.B. Ferreira

5.1 Introduction 2935.2 Asymmetric Induction Using Chiral Ketones 2955.2.1 1,4-Asymmetric Induction Using α-Alkyl Ketones 2965.2.2 1,4-Asymmetric Induction Using α-Methyl-β-Branched Ketones 3025.2.3 1,4-Asymmetric Induction Using α-Alkoxy Ketones 3055.2.4 1,5-Asymmetric Induction Using β-Alkoxy Methyl Ketones 3135.2.5 1,6-Asymmetric Induction Using Chiral Methyl Ketones 3175.3 Asymmetric Induction Using Chiral Aldehydes 3175.3.1 1,2-Asymmetric Induction Using Chiral Aldehydes 3175.3.2 1,3-Asymmetric Induction Using Chiral Aldehydes 3355.3.3 Asymmetric Induction Using α-Methyl-β-Alkoxy Aldehydes 3425.3.4 Asymmetric Induction Using α,β-Bisalkoxy Aldehydes 3575.4 Asymmetric Induction in the Aldol Addition of Chiral Enolates to Chiral

Aldehydes 360References 371

6 Polypropionate Synthesis via Substrate-Controlled Stereoselective AldolCouplings of Chiral Fragments 377Dale E. Ward

6.1 Introduction 3776.2 Principles of Stereoselective Aldol Reactions 3786.2.1 Relative Topicity 3786.2.2 Chiral Reactants 3816.2.2.1 Diastereoface Selectivity of Chiral Ethyl Ketones 3816.2.2.2 Diastereoface Selectivity of Chiral Aldehydes 3866.2.2.3 Multiplicativity Rule 3946.3 Stereoselective Aldol Coupling of Chiral Reactants 3986.3.1 2-Alkoxy-1-Methylethyl Ethyl Ketones: Paterson’s Dipropionate

Equivalent 3986.3.1.1 Reactions with Achiral Aldehydes 3986.3.1.2 Reactions with Chiral Aldehydes 4006.3.2 1-Methylalkyl Ethyl Ketones: 3-Deoxy Polypropionate Equivalents 4026.4 2-Alkoxyalkyl Ethyl Ketones: 2-Desmethyl Polypropionate

Equivalents 4066.4.1 2-Alkoxy-1-Methylalkyl Ethyl Ketones: Polypropionate Equivalents 4096.4.1.1 (E) Boron Enolates 4116.4.1.2 (Z) Boron Enolates 412

Contents IX

6.4.1.3 Silyl Enolates 4136.4.1.4 Lithium Enolates 4146.4.1.5 Titanium Enolates 4166.4.1.6 Tin Enolates 4196.5 Conclusions 420

References 424

7 Application of Oxazolidinethiones and Thiazolidinethiones in AldolAdditions 431Michael T. Crimmins

7.1 Introduction 4317.2 Preparation of Oxazolidinethione and Thiazolidinethione Chiral

Auxiliaries 4317.3 Acylation of Oxazolidinethione and Thiazolidinethione Chiral

Auxiliaries 4337.4 Propionate Aldol Additions 4347.5 Acetate Aldol Additions 4377.6 Glycolate Aldol Additions 4437.6.1 Synthetic Applications of Aldol Additions of N-Propionyl

Oxazolidinethiones and Thiazolidinethiones and Their SubstitutedVariants 443

7.6.2 Synthetic Applications of Aldol Additions of N-Acetyloxazolidinethionesand Thiazolidinethiones 461

7.6.3 Synthetic Applications of anti-Aldol Additions ofN-Glycolyloxazolidinethiones 466References 471

8 Enzyme-Catalyzed Aldol Additions 475Pere Clapes and Jesus Joglar

8.1 Introduction 4758.2 Pyruvate Aldolases 4778.3 N-Acetylneuraminic Acid Aldolase (NeuA) 4788.3.1 Novel NeuA Biocatalyst by Protein Engineering 4828.3.2 Large-Scale Process 4868.3.3 Related Pyruvate Aldolases/2-Oxobutyrate Aldolases 4878.4 Dihydroxyacetone Phosphate (DHAP) Aldolases 4948.4.1 Structure and Mechanism 5008.4.2 L-Rhamnulose-1-Phosphate Aldolase as a DHA-Dependent

Aldolase 5028.5 D-Fructose-6-Phosphate Aldolase and Transaldolase B Phe178Tyr:

FSA-Like Aldolases 5038.6 2-Deoxy-D-Ribose-5-Phosphate Aldolase (RibA or DERA; EC

4.1.2.4) 5108.7 Glycine/Alanine Aldolases 5148.8 Aldol Reactions Catalyzed by Non aldolases 520

X Contents

8.9 Conclusions and Perspectives 5208.9.1 Substrate Tolerance/Stereoselectivity 5218.9.2 Future Perspectives 521

References 522

Index 529

XI

Preface

Stereoselectivity is one of the most important aspects for natural product chemists.Following the increasing possibility of detection and assignment of stereogeniccenters, a tremendous increase in stereoselective methods of organic reactions,particularly aldol reactions, has been noticed. In the beginning of this development,only sporadic examples of stereoselective aldol reactions were described, mostly inthe context of total syntheses of natural products. An outstanding early exampleis the R. B. Woodward’s proline-catalyzed aldol addition in the total synthesis oferythronolide A at the Harvard University in 1981. In the following three decades,a vast arsenal of stereoselective aldol additions has been developed (see Figure).

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This book provides a compre-hensive review of modern aldolreactions, especially in the aspectof how to achieve high stereos-electivity – diastereoselectivity aswell as enantioselectivity. Stereos-election is discussed under severaldifferent aspects. One aspect is thedeployment of different substrates –acetate or propionate aldol reactions.Another aspect is the mode of actionincluding metal enolate chemistry,Lewis acid as well as Lewis basecatalysis, enzymatic catalysis, andorganocatalysis. There are someoverlappings of these aspects in thechapters covering the cross-cuttingthemes of vinyloguos Mukaiyama reaction or asymmetric inductions (e.g., com-pare Scheme 1.50 with Scheme 2.59) or total synthesis of dolastatin 19 – (compareScheme 1.82 with Scheme 5.8). These overlappings, however, are intentional inorder to give a comprehensive insight into the techniques for installing requiredconfigurations during aldol reactions. The utility of the corresponding methodsis shown in the context of total syntheses of natural products. All chapters arethoroughly well written by experts in the respective fields.

XII Preface

It is my pleasure to express profound gratitude to the 15 authors for their hugeendeavor to organize and summarize this vast amount of material. It has been agreat pleasure for me to work with this team of authors at all times. Finally, myspecial thanks go to Elke Maase and Bernadette Gmeiner at WILEY for their finework in making this book a reality.

Berlin, Autumn 2012 Rainer Mahrwald

XIII

List of Contributors

Patrick B. BradyThe University of ChicagoDepartment of Chemistry5735 S. Ellis Ave. (GHJ 409)ChicagoIllinois 60637USA

Pere ClapesInstituto de Quımica Avanzada deCatalunaConsejo Superior deInvestigaciones Cientıficas(IQAC-CSIC)Departmento de QuımicaBiologica y ModelizacionMolecularJordi Girona 18-2608034 BarcelonaSpain

Martin CordesLeibniz Universitat HannoverCenter for Biomolecular DrugResearchSchneiderberg 1 B30167 HannoverGermany

Michael T. CrimminsUniversity of North Carolina atChapel HillKenan LaboratoriesChapel HillNC 27599USA

Luiz C. DiasUniversity of CampinasUNICAMPInstitute of ChemistryC.P. 615413083-970 CampinasSao PauloBrazil

Marco A. B. FerreiraUniversity of CampinasUNICAMPInstitute of ChemistryC.P. 615413083-970 CampinasSao PauloBrazil