Chiral oxazaborolidinium ion activated carboxylic acids and aldimines : catalytic enantioselective protonation/nucleophilic addition, strecker and povarov reactions

다국어 초록 (Multilingual Abstract)

Chiral boron Lewis acid catalyst has a long history and the enantioselective synthetic method. It is a useful and versatile synthetic method for the stereoselective generation of chiral centers. Since it was first reported by Corey et al., chiral oxazaborolidinium ions (COBI), active forms of oxazaborolidine derived from proline, have been used as powerful Lewis acid catalysts. Initially, enantioselective Diels-Alder reaction catalyzed by COBI was reported, followed by nucleophilic 1,2- or 1,4-additions and cycloaddition reactions of various carbonyl compounds. Then corresponding tandem reactions were mainly developed.
In this thesis, catalytic enantioselective protonation/nucleophilic addition with carboxylic acids was studied. Catalytic tandem reactions involving an enantioselective protonation step provide a powerful tool for the construction of structurally complex chiral molecules. A new chiral Brønsted acid derived from carboxylic acid and a chiral oxazaborolidinium ion (COBI), as an activator, is introduced. This acid was successfully applied as a catalyst for the highly enantioselective protonation/nucleophilic addition of diazoesters with carboxylic acids. This mild and chemoselective transition-metal-free coupling reaction provides access to a variety of α- or β-acyloxy esters in good yields and high to excellent enantioselectivities. The resulting α- or β-acyloxy esters can easily be converted into enantioenriched (S)-tropic acid methyl ester without loss of optical purity.
Next, chiral oxazaborolidinium ion (COBI)-catalyzed enantioselective nucleophilic addition reactions of aldimines using tributyltin cyanide and have been developed. Various α-aminonitriles was synthesized in high yield (up to 98%) with high to excellent enantioselectivity (up to 99% ee). A rational mechanistic model for the complex of COBI and aldimine is provided to account for these enantioselective reaction.
Finally, a new catalytic enantioselective Povarov reaction of imine was successfully developed. Chiral tetrahydroquinoline cores are characteristic structural motifs in many biologically active natural products and pharmacologically relevant therapeutics. A synthesis of chiral functionalized tetrahydroquinolines has been developed by means of catalytic enantioselective Povarov reaction of aldimines with various alkenes in the presence of a chiral COBI catalyst. The reaction gave the corresponding highly functionalized tetrahydroquinolines in good yields, excellent diastereoselectivities (>20:1 dr), and high enantioselectivities (up to 98% ee).
This thesis summarizes recent research of catalytic enantioselective protonation/nucleophilic addition, Strecker and Povarov reactions catalyzed by COBI catalysts.

목차 (Table of Contents)

• 1. Introduction 1
• 1.1. Chiral Lewis Acid Catalysis 1
• 1.2. Chiral Boron Lewis Acid Catalysis 2
• 1.3. Chiral Oxazaborolidinium Ion (COBI) Catalyst 3
• 1.4. References 5
• 2. Catalytic Enantioselective Protonation/Nucleophilic Addition of Diazoesters with Chiral Oxazaborolidinium Ion Activated Carboxylic Acid 7
• 2.1. Introduction of Diazocompound in Organic Synthesis 7
• 2.2. Introduction of Enantioselective Protonation 9
• 2.3. Results and Discussion 13
• 2.4. Conclusion 22
• 2.5. Experimental Section 23
• 2.5.1. General Information 23
• 2.5.2. Preparation of α-benzyl diazoesters 23
• 2.5.3. Preparation of Chiral Oxazaborolidinium Ion (COBI) Catalyst 24
• 2.5.4. General Procedure for Enantioselective Protonation-Nucleophilic Addition 25
• 2.5.5. Characterization of Chiral α- or β-acyloxy esters 25
• 2.5.6. Transformation of adduct 2a to (S)-methyl 3-hydroxy-2-phenylpropanoate (4) 44
• 2.5.7. Gram-Scale Experiment 45
• 2.5.8. Kinetic Isotope Effect Experiment 46
• 2.5.9. Assignment of Absolute Configuration 46
• 2.6. References 47
• 3. Enantioselective Strecker Reaction with Aldimines Catalyzed by Chiral Oxazaborolidinium Ions 50
• 3.1. Introduction 50
• 3.2. Introduction of Strecker Reaction 51
• 3.3. Result and Discussion 56
• 3.4. Conclusion 64
• 3.5. Experimental Section 65
• 3.5.1. General Information 65
• 3.5.2. Preparation of Chiral Oxazaborolidinium Ion (COBI) 1 65
• 3.5.3. Preparation of Aldimines 2 66
• 3.5.4. General Procedure for Enantioselective Strecker Reaction 66
• 3.5.5. Characterization of Chiral α-Aminonitriles 4 67
• 3.5.6. Transformation of a Chiral α-Aminonitrile 79
• 3.5.7. Formal Synthesis of (S)-Levamisole 81
• 3.5.8. Assignment of Absolute Configuration 84
• 3.6. References 86
• 4. Enantioselective Povarov Reaction with Aldimines Catalyzed by Chiral Oxazaborolidinium Ions 90
• 4.1. Introduction of Povarov Reaction 90
• 4.2. Result and Discussion 94
• 4.3. Conclusion 97
• 4.4. Experimental Section 98
• 4.4.1. General Information 98
• 4.4.2. Preparation of Chiral Oxazaborolidinium Ion (COBI) 1 98
• 4.4.3. Preparation of Aldimines 2 99
• 4.4.4. General Procedure for Enantioselective Povarov Reaction 99
• 4.4.5. Characterization of Chiral Tetrahydroquinoline Derivatives 4 100
• 4.5. References 101
• 5. Summary 103
• 5.1. Catalytic Enantioselective Protonation/Nucleophilic Addition of Diazoesters with Chiral Oxazaborolidinium Ion Activated Carboxylic Acid 103
• 5.2. Enantioselective Strecker Reaction with Aldimines Catalyzed by Chiral Oxazaborolidinium Ions 104
• 5.3. Enantioselective Povarov Reaction with Aldimines Catalyzed by Chiral Oxazaborolidinium Ions 105