Development of a Copper Catalyzed Aminoacetoxylation Reaction of Olefins, Development of an Intermolecular and Diastereoselective Iminium Cascade Reaction and Studies Towards the Synthesis of a Malagasy Alkaloid Open Access

Mancheno, Danny Emilio (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/x633f126n?locale=en
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Abstract

Nitrogen heterocycles are important intermediates in the synthesis of medicinal compounds, agricultural chemicals, polymers and analytical reagents. Although, there are several approaches to the synthesis of nitrogen heterocyles, a lot of challenges still remain. Moreover, the recent demand by society to develop more environmentally and economically friendly synthetic methods has given rebirth to the need for new methodologies across organic chemistry. Thus, a lot emphasis has been directed towards the development of new and mild conditions for the formation of nitrogen heterocycles. Since its inception, the Blakey lab has been working on developing new methods for synthesis of nitrogen heterocycles. With that aim, we have developed new methodology that involves metallonitrenes intermediates for the formation of carbon-nitrogen bonds. Additionally, our lab has also developed an iminium based cascade annulation reaction for the synthesis of the structural cores of some unusual strychnos alkaloids. Three main projects that have branched out of this initial work will be discussed in this thesis: the development of a copper catalyzed aminoacetoxylation reaction of olefins (part 1); development of a diastereoselective intermolecular cascade annulation reaction (part 2) and application of the intramolecular cascade cyclization reaction towards the total synthesis of a Malagasy alkaloid (part 3).

Table of Contents

Table of Contents

1 Chapter One: Introduction to Vicinal Amino Alcohols and Aminohydroxylation Reactions 2

1.1 Vicinal Amino Alcohols.......................................................................................... 2

1.2 Aminohydroxylation Reactions.............................................................................. 3

1.2.1 Osmium Catalyzed Aminohydroxylation Reactions....................................... 4

1.2.2 Palladium Catalyzed Aminohydroxylation Reactions..................................... 5

1.2.3 Copper Catalyzed Amino-oxygenation Reactions.......................................... 7

1.2.4 Gold Catalyzed Amino-oxygenation Reactions.............................................. 8

1.2.5 Metal Free Amino-oxygenation Reactions...................................................... 9

1.2.6 Blakey's Group Entry into Amino-oxygenation Reactions.......................... 10

2 Chapter Two: Copper Catalyzed Aminoacetoxylation of Olefins...................... 12

2.1 Synthesis of Sulfonamide 3.................................................................................. 12

2.1.1 Initial Synthesis of Sulfonamide 3................................................................. 12

2.1.2 New Synthesis of Sulfonamide 3................................................................... 13

2.2 Initial Investigations............................................................................................. 14

2.3 Optimization Studies............................................................................................ 16

2.3.1 NMR Assay.................................................................................................. 16

2.3.2 Oxidant Optimization and Activating Group Optimization......................... 16

2.3.3 Base and Catalyst Optimization................................................................... 17

2.3.4 Solvent Optimization.................................................................................... 18

2.4 Intermolecular aminoacetoxylation of γ-aminoolefins.......................................... 19

2.4.1 Terminal Olefins............................................................................................ 19

2.4.2 Mechanism.................................................................................................... 25

2.4.3 Aminoacetoxylation of 1,2 disubstituted olefins........................................... 26

2.5 Conclusions and Future Work.............................................................................. 32

3 Chapter Three: Introduction to the Banyaside Alkaloids................................... 35

3.1 Banyaside A and B: Isolation, Structure and Stereochemistry............................. 35

3.2 Biological Activity................................................................................................ 37

3.3 Carreira's Syntheis of Banyaside B...................................................................... 38

3.4 Our Approach to the Core of the Banyaside Alkaloids....................................... 40

4 Chapter Four: Development of an Intermolecular Imminium Cascade Reaction for the Synthesis of the Banyaside Core 43

4.1 Early Attempts with N-Tosyl-O-TMS Aminol 77............................................. 43

4.1.1 Synthesis of α,β unsaturated acid 86............................................................. 43

4.1.2 Synthesis of N-Tosyl-O-TMS aminol 77..................................................... 48

4.1.3 Cascade Annulation with N-Tosyl-O-TMS aminol 77................................. 49

4.2 Intermolecular Iminium Cascade with N-Cbz-O-TMS Aminol 99...................... 49

4.2.1 Synthesis of N-Cbz-O-TMS aminol 37........................................................ 49

4.2.2 Cascade Annulation of N-Cbz-O-TMS aminol 99........................................ 50

4.2.3 Synthesis of N-benzyl-cyclohexanol 103...................................................... 53

4.2.4 Synthesis of N-methyl-cyclohexanol 104...................................................... 54

4.2.5 Synthesis of N-benzyl-O-TBDMS-cyclohexanol 106.................................. 54

4.2.6 Proposed Transition State for the Cyclization of 99.................................... 56

5 Chapter Five: Studies Towards an Enantioselective Intermolecular Cascade Reaction...58

5.1 Introduction.......................................................................................................... 58

5.2 Thiourea Based Catalysts (Hydrogen-Bonding Catalysts).................................. 59

5.3 Investigations into thioureas as catalysts for our methodology........................... 63

5.3.1 Synthesis of chiral thiourea 58...................................................................... 63

5.3.2 Iminium Cascade Reaction with Sulfonic Acids............................................ 65

5.3.3 Cyclization with chiral thiourea catalyst 58.................................................. 66

5.4 Ti(IV) based catalyst............................................................................................ 67

5.4.1 Braun's dynamic kinetic asymmetric allylations........................................... 67

5.4.2 Synthesis of Ti(IV) Catalyst 130.................................................................. 68

5.4.3 Synthesis and Allylation of 65...................................................................... 71

5.5 Conclusions.......................................................................................................... 72

6 Chapter Six: Introduction to the Malagasy Alkaloids and Initial Efforts Towards the Syntheis of Malagashanine 77

6.1 The Malagasy Alkaloids....................................................................................... 77

6.2 Malagashanine: Structure...................................................................................... 78

6.3 Myrtoidine and Demethoxymyrtoidine............................................................... 79

6.3.1 Myrtoidine.................................................................................................... 79

6.3.2 11-Dimethoxymyrtoidine.............................................................................. 80

6.4 Biological Activity................................................................................................ 80

6.5 Blakey's Lab Approach to the Malagasy Alkaloids............................................ 83

6.5.1 Early Cascade Annulation Work................................................................... 83

6.5.2 Extending the Scope of Methodology to Incorporate the C(16) Stereocenter. 84

6.5.3 Synthesis of Advanced Pyran 166................................................................ 85

7 Chapter Seven: Total Synthesis of Epi-malagashanine...................................... 88

7.1 Development of a Scalable Route for the Synthesis of Key Dihydropyran 169. 88

7.1.1 Synthesis of N-Tosyl-amide161................................................................... 88

7.1.2 Optimization Studies for the Synthesis of N-Tosyl-O-TMS aminol 161, Imidazole as a Mild Lewis Acid. 90

7.1.3 Key intramolecular cascade reaction.............................................................. 93

7.1.4 Synthesis of dihydropyran 175..................................................................... 93

7.2 Synthesis of Ester 182: Original Approach and New Approach Circumventing the Problematic Oxidation Step. 95

7.2.1 Original Approach to Methyl-Ester 184....................................................... 95

7.2.2 Second Generation Approach to Methyl-ester 184...................................... 97

7.2.3 Third Generation Approach to Methyl-Ester 184. Trifluoroacetic anhydride as a Carbonyl Source. 99

7.2.4 Fourth Generation Approach to Methyl Ester 184.................................... 102

7.3 Reduction of the C(19)-C(20) Tetrasubstituted Olefin of Methyl Ester 184.... 104

7.3.1 Hydrogenation on Model System............................................................... 104

7.3.2 Hydrogenation of the C(19)-C(20) Tetrasubstituted Olefin of Acid 183 and Ester 184. 105

7.4 Ionic Reduction of the C(19)-C(20) Tetrasubstituted Olefin............................. 107

7.5 Synthesis of Epi-Malagashanine; Removal of the Nb Tosyl Auxiliary and Reductive Methylation. 109

8 Chapter Eight: Efforts Towards the Synthesis of 11-Demethoxymyrtoidine and a New Strategy Towards Malagashanine 111

8.1 First Generation Strategy Towards the Synthesis of 11-demethoxymyrtoidine (154) and New Strategy Towards Malagashanine (151). 111

8.1.1 First Generation Strategy Towards Demethoxymyrtoidine by Direct C-H functionalization 111

8.1.2 New Approach to Malagashanine from Intermediate 210.......................... 112

8.1.3 Allylic Halogenation of Methyl-ester 182.................................................. 113

8.1.4 Allyl Oxidation via an Extended Enolate..................................................... 114

8.1.5 Oxidation via C-H activation....................................................................... 118

8.2 Second Generation Approach: Introduction of the Oxygen Atom via Hydroacylation with Acetoxyacetyl Chloride 119

8.2.1 Retrosynthetic Analysis.............................................................................. 119

8.2.2 Initial Synthesis of dihydropyran 234........................................................ 120

8.2.3 Acylation of Dihydropyran 242................................................................. 122

8.2.4 Vilsmeier-Haack Formylation...................................................................... 124

8.3 Third-generation Approach: Synthesis of Tetronic Acid................................... 127

8.3.1 Retrosynthetic Analysis.............................................................................. 127

8.3.2 Hydrolysis of α-Acetoxy Ketone 239......................................................... 128

8.3.3 Attempts to Synthesize Tetronic Acid 259................................................ 129

8.4 Conclusions........................................................................................................ 132

9 Experimentals.......................................................................................................... 134

9.1 Materials and Methods: General Information.................................................... 134

9.2 Part 1: Copper Catalyzed Aminoacetoxylations of Olefins............................... 135

9.3 NMR Spectra-Part 1.......................................................................................... 153

9.4 Part 2: Efforts Towards the Development of an Enantioselective Intermolecular Cascade Reaction to Access the Core of the Banyaside Peptides. 160

9.5 NMR Spectra Part 2........................................................................................... 173

9.6 Part 3. Studies Towards the Total Synthesis of a Malagasy Alkaloid............... 176

9.7 X-ray Structures-Part 3...................................................................................... 203

10 References................................................................................................................ 252


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