Explorations of Metallocarbene and Metallonitrene Reactive Intermediate Chemistry for the Development of Synthetically Useful New Reactions Open Access

Abstract

Explorations of Metallocarbene and Metallonitrene Reactive Intermediate Chemistry for
the Development of Synthetically Useful New Reactions
By
Véronique Martin


This dissertation outlines our efforts on three different projects focusing on the
synthesis of metallocarbene and metallonitrene intermediates for the development of new
reactions. Part I focuses on a proposed novel carbohydroxylation reaction through an
osmium (VIII) alkylidene intermediate. We were able to synthesize a series of
unprecendented high oxidation state osmium alkylidene complexes by reaction of bis
imido osmium (VIII) complexes with bulky electron ylides. We also demonstrated that
these alkylidenes undergo a [3+2] reaction with nitrones to generate an alkene product.
Part II focuses on the expansion of the substrate scope of our newly developed
metallonitrene/ alkyne reaction. In the context of C-N bond formation, we were able to
demonstrate that this reaction is versatile and leads to the formation of new C-C, C-N and
C-O bonds to give rise to a variety of complex products from relatively simple starting
materials. This work has led us to explore the mechanism of this reaction and allowed us
to hypothesize on the nature of the reactive intermediate. In addition, we also studied the
chemoselectivity of different Rh(II) catalysts. Part III focuses on our efforts towards the
concise synthesis of (+)-actinobolin through a key selective C-H insertion step to form a
6-membered ring product. We propose to impart this unusual selectivity through the
careful choice of protecting groups on the C5-C6 diol. So far, protection as the acetonide
leads to the formation of cyclobutanone products. Protection with electron-withdrawing
groups and exploring the selectivity of Rh(II) catalysts is now the focus of this project.

Table of Contents

Table of Contents

Part I: Synthesis and Reactivity of Osmium (VIII) Alkylidene Complexes. 1

1. Chapter One: Introduction. 1

1.1. Difunctionalization of Olefins in Total Synthesis. 1

1.2. A Proposed Carbohydroxylation Reaction. 3

1.3. Difunctionalization of Olefins using Osmium Reagents. 3

1.3.1 Dihydroxylation of Olefins. 3

1.3.2 Aminohydroxylation of Olefins. 5

1.3.3 Diamination of Olefins. 7

1.4. Imido Osmium Complexes. 8

1.5. High Oxidation State Alkylidene Complexes. 11

1.6. Theoretical studies. 14

2. Chapter Two: Results and Discussion 16

2.1. Initial Approach: Diazo Compounds as Alkylidene Transfer Reagents. 16

2.2. Various Approaches for the Synthesis of Osmium (VIII) Alkylidene Complexes. 17

2.2.1 Results with Osmium Tetroxide. 18

2.2.2 Introduction of Imido Ligands. 19

2.2.3 Synthesis of Phosphorous Ylides. 20

2.2.4 Results with Monoimido Complex 8 .23

2.2.5 Results with Bisimido Complexes 6 and 14 .23

2.2.6 Results with Trisimido Complexes 9 and 12 .25

2.2.7 Reaction Optimization 27

2.3. Approaches to Stabilize The Alkylidene Complex. 28

2.3.1 Modification of the Imido Ligand. 28

2.3.2 Polymerization of the Phosphorous Ylide. 30

2.3.3 Intramolecular Approach. 33

2.4. Investigations into the Reactivity of the Alkylidene Complex 36

2.4.1 Reactivity with Olefins. 37

2.4.2 Alternative Trapping Reagents. 37

2.4.3 Reaction with Nitrones. 38

2.5. Conclusions. 39

3. Chapter Three: Experimentals. 41

3.1. Materials and Methods: General Information. 41

3.2. General Procedures. 42

3.3. Procedures and Compound Characterization. 43

Part II: Studies on the versatility of metallonitrene/ alkyne cascade reactions. 58

4. Chapter Four: Introduction. 58

4.1. N -containing Compounds in Chemistry.58

4.2. The Chemistry of Metallonitrenes. 59

4.2.1 Aziridination. 59

4.2.2 C-H Amination. 62

4.3. Dirhodium(II) Paddlewheel Complexes. 65

4.4. Metallonitrene Chemistry and Metallocarbene Chemistry: a Comparison. 69

4.5. Development of a metallonitrene/ alkyne cascade reaction. 70

4.5.1 Proposed reaction. 70

4.5.2 Metallonitrene/ Alkyene Cascade Reactions: Preliminary results. 71

4.5.3 Reaction Scope. 72

4.5.4 Nature of the Reactive Intermediate. 73

5. Chapter Five: Results and Discussion. 74

5.1. Preliminary Results. 74

5.2. Synthesis of the Starting Homopropargylic Sulfamate Esters. 75

5.2.1 Initial Approach. 75

5.2.2 Alternative Route to Access the Homopropargylic Esters. 77

5.2.3 Elongation of the Tether Between the Alkyne and the Nucleophile. 79

5.3. Cyclization Reactions with p -Nucleophiles. 81

5.3.1 Formation of 7,5-Ring Systems. 81

5.3.2 Formation of 7,6-Ring Systems. 83

5.3.3 Nature of the Reactive Intermediate. 86

5.4. Synthesis of Pyrrolidine Substrates. 87

5.5. Efforts to Develop an Enantioselective Version of Our Metallonitrene/ Alkyne Reaction. 88

5.5.1 Enantioselectivity studies of the metallonitrene/ alkyne oxonium ylide cascade with substrate 50 .89

5.5.2 Enantioselectivity studies of the metallonitrene/ alkyne cyclopropanation cascade with substrate 18 .90

5.5.3 Enantioselectivity studies of the metallonitrene/ alkyne cyclopropanation cascade with substrates 29 and 30 .91

5.6. Tuning the Selectivity via Catalyst Development. 94

5.6.1 Objectives of Catalyst Development. 94

5.6.2 Carbamates as Nitrene Precursors in the Metallonitrene/ Alkyne Reaction… 95

5.6.3 Chemoselectivity Studies With Rh(II) Tetracarboxylate Complexes. 96

5.6.4 Chemoselectivity Studies With a Rh(II) Tetracarboxamidate Catalyst. 100

5.6.5 Catalyst Design. 101

5.6.6 Synthesis of Ligand 69 .103

5.6.7 Chemoselectivity Studies With Newly Developed Catalyst 76 .106

5.7. Conclusions. 107

6. Chapter Six: Experimentals. 109

6.1. Materials and Methods : General information. 109

6.2. General Procedures. 110

6.3. Procedures and Compound Characterization. 112

6.4. X-Ray Crystallograghy. 152

Part III: Studies towards the synthesis of (+)-Actinobolin. 183

7. Chapter Seven: Introduction. 183

7.1. Actinobolin and Bactobolin. 183

7.1.1 Actinobolin: Isolation, Characterization and Biological Acitivity. 183

7.1.2 Bactobolin: a Related Compound. 184

7.2. Syntheses of (+)-actinobolin and (-)-bactobolin. 185

7.2.1 Syntheses of (+)-actinobolin via a Diels Alder reaction.185

7.2.2 Weinreb's Approach to (+)-Actinobolin and (-)-Bactobolin. 189

7.3. Approach to (+)-Actinobolin and Our Interest in this Natural Product. 193

7.3.1 Retrosynthetic Analysis. 193

7.3.2 Amino-oxygenation of an Alkene. 194

7.3.3 Regio- and Diastereoselective C-H Insertion Reaction. 195

7.3.4 Retrosynthesis of a -Diazo b -Ketoester 45 .198

8. Chapter Eight: Results and Discussion. 199

8.1. Diastereoselectivity of the Mukaiyama Aldol Reaction. 199

8.1.1 Mukaiyama Aldol Reactions with Diene 51 and a -Heterosusbtituted Aldehydes. 199

8.1.2 (-)-Pestalotin 52 and epi- Pestalotin 53 as a Model System.200

8.1.3 Determination of the Diastereoselectivity in a Model System. 202

8.2. First Approach to (+)-Actinobolin using the Electron-Withdrawing Group Strategy. 203

8.2.1 Determination of the diastereoselectivity with a -hydroxyaldehyde 61 .203

8.2.2 Moving forward with the synthesis of (+)-actinobolin. 204

8.2.3 Switching protecting group for the synthesis of a -diazo b -ketoester 45 .206

8.2.4 Changing the order of addition of the electron-withdrawing protecting group… 209

8.3. Second Approach to the Synthesis of (+)-Actinobolin using the Acetonide Protecting Group Strategy. 211

8.3.1 Synthesis of a -diazo b -ketoester 77 .211

8.3.2 Cyclization reaction of a -diazo b -ketoester 77 .212

8.3.3 Synthesis and cyclization reaction of a -diazo b -ketoester 82 .213

8.3.4 Alternative strategies. 216

8.4. Conclusions and Future Work. 218

9. Chapter Nine: Experimentals. 220

9.1. Materials and Methods : General information. 220

9.2. General Procedures. 221

9.3. Procedures and Compound Characterization. 223

10. References. 256

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	metallonitrene/alkyne cascade reactions synthesis of actinobolin high oxidation state alkylidene complex osmium (VIII) alkylidene complex regio- and diastereoselective C-H insertion
Committee Chair / Thesis Advisor	Blakey, Simon, Emory University
Committee Members	McDonald, Frank, Emory University Liebeskind, Lanny S, Emory University

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