Group IX Metal-Catalyzed C–H Activation Towards the Development of New Synthetic Strategies Open Access

Abstract

Part 1 of this dissertation describes efforts leading to the development of a new class of chiral dienes, specifically C2 symmetric cyclooctadienes (CODs). Proven to be formidable ligands for asymmetric catalysis in recent years these ligands were limited to 1,5 disubstituted scaffolds historically. Through collaboration with the Davies Group at Emory University, previously unreported 3,7 disubstituted CODs were accessed in one step and subsequently diversified. The in-situ development of a homogeneous rhodium catalyst with these ligands for enantioselective C(sp3)–H functionalization is described.

Part 2 of this dissertation addresses efforts to provide modern small molecule discovery with novel heterocyclic moieties for new cutting-edge agrochemicals and pharmaceuticals. Leveraging late-stage functionalization of C–H bonds has become increasingly powerful to target these moieties, however, non-directed activation of desired C–H bonds remain challenging. In response to this limitation, the design and use of directing groups has become extremely important despite their shortcomings. Previously, oxidative addition has been employed for directed annulations, but analogous reactivity with transmetallation has remained underexplored. Currently, we have developed new methodology to leverage transmetallation of boryl species to promote distal C(sp2)–H activation and subsequent functionalization.

Part 3 of this dissertation describes the effort of the Blakey Lab to adopt and pioneer new sustainable and green processes in the chemistry lab. Through continual commitment to reducing our environmental and carbon footprints, the Blakey lab has changed how we fundamentally operate day-to-day to lower or resource consumption and extend the life our consumables. This has led to several invaluable advancements in the understanding of energy consumption, water usage and waste production. Furthermore, quantitative data was collected to highlight the benefit for investing in new heat/stir plates and aluminum heating blocks.

Table of Contents

Part 1: Design and Application of Chiral Diene Systems via Iterative C–H Functionalization Chapter 1: Historical Perspective, Synthesis, and Catalytic Application of Chiral Diene Ligands 1

1.1         Introduction to Chiral Olefins 2

1.1.1   Brief History of Metal-Olefin Catalysis 2

 1.1.2   Scaffolds and Their Peculiarities 5

1.2         Accessibility and Application of Chiral Dienes in Asymmetric Catalysis 8

 1.2.1 Selected Syntheses of Common Chiral Diene Scaffolds 8

1.2.2  Methods Utilized to Acquire Enantiopure Ligands 13

1.2.3   Selected Applications in Asymmetric Catalysis 15

1.3        Concluding Remarks 19

1.4        References 20

Chapter 2: Leveraging C–H Functionalization for Synthesis of Chiral C2 symmetric 1,5-Cyclootadienes (COD) Ligands 26

2.1    Introduction to Chiral C2 symmetric 1,5-COD Ligands 27

2.1.1 Brief History of Blakey Lab Catalysis 27

2.1.2   Collaboration on Novel C1–Symmetric COD Compounds for Diastereomeric Resolution of Indenyl Catalysts 29

2.2   Generation of Chiral C2–symmetric 1,5-COD Ligands and Evaluation in Asymmetric Catalysis 30

2.2.1   Collaboration on Novel C2–Symmetric COD Compounds for Diastereomeric Resolution of Indenyl Catalysts 30

2.2.2   Evaluation of C2–Symmetric COD Compounds in a Hayashi-Miyaura Reaction 32

2.2.3   2.2.3 Evaluation of C2–Symmetric COD Compounds in a α-Diazoester Insertion Reactions 38

2.3   Concluding Remarks 40

2.4   References 41

2.5   Experimental Section 43

2.5.1   General Information 44

2.5.2   Procedures and Tabulated Data 44

Part 2: Applications of Transmetallation in Group IX Metal Catalysis

Chapter 3: Introduction to Traceless C–H Directing Groups 65

3.1   Introduction to Directed Metal C–H Functionalization 66

3.1.1   Brief History of Directed Metal C–H Functionalization 66

3.2   Current Directing Groups Strategy in C–H Functionalization 70

3.2.1   Permanent Directing Groups and Their Removal 70

3.2.2   Transient Directing Group Strategy and Pitfalls 75

3.2.3   Traceless Directing Group Strategy and Current State of the Art 79

3.3   Concluding Remarks 85

3.4   References 86

Chapter 4: Leveraging α-Amino Boron Species for the Synthesis 1,2-Dihydroquinolines Scaffolds via C–H Annulation 93

4.1   Introduction to Transmetallation as a C–H Functionalization Strategy for Annulation 94

4.1.1   Initial Investigations into Transmetallation Directed C–H Functionalization 94

4.1.2   Early Development and Testing of α-Amino Boronic Acid Esters 97

4.2   Exploration of Expansion Partners and Further Development of Aryl α-Amino Boronic Species 105

4.2.1    Screening for Competence of Migratory Insertion Partners 105

4.2.2    Generation of α-Amino Boronic Species and Evaluation in Optimized Conditions 107

4.2.3    Revisiting Optimization of The Rhodium Catalyzed System Prior to Implementation 110

4.3     Evaluating the Scope of This Methodology and Inherit Limitations of the System 112

4.3.1   Scope of Aryl α-Amino Boronic Acid Pinacol Esters with Diphenylacetylene 112

4.3.2    Scope of (Hetero)Aryl α-Amino Boronic Acid Pinacol Esters with Diphenylacetylene 114

4.3.3    Scope of (Hetero)Aryl Alkynes with (4-CF3)-Ph α-Amino Boronic Acid Pinacol Ester 116

4.3.4    Scope of Alkyl- Aryl Alkynes with (4-CF3)-Ph α-Amino Boronic Acid Pinacol Ester 118

4.3.5    Diversification of 1,2-Dihydroquinolines and Further Experiments 121

4.4   Concluding Remarks 125

4.5   References 127

4.6   Experimental Section 129

4.5.1   General Information 129

4.5.2   Procedure and Tabulated Data 132

4.5.3   Supplementary References 180

Chapter 5: Developing a Scalable and Chromatography-Free Route Towards a Safe 1,2-Carboamidation Substrate for Peptide Macrocyclization 183

5.1   Introduction to 1,2-Carboamidation Methodology and Transfer Substrate Development 184

5.1.1   Brief History of the Blakey Lab’s Cobalt Catalyzed 1,2-Carboamidation of Acrylamides 184

5.1.2   Preparation of the Tyrosine 1,2-Carboamidation Substrate 185

5.1.3  Remaining Challenges for the Tyrosine 1,2-Carboamidation Substrate 191

5.3   Concluding Remarks 192

5.4   References 194

5.5   Experimental Section 195

5.5.1   General Information 195

5.5.2   Procedures 196

5.5.3   Supplementary References 200

Part 3: Implementation of Green Chemistry Lab Principles

Chapter 6: Advancing the Green Lab’s Directive at Emory University in the Blakey Lab 201

6.1   Introduction to Green Lab Initiatives in the Blakey Lab 202

6.1.1   Brief History of Blakey Lab Green Lab Initiatives 202

6.1.2   Identification and Implementation of Water, Acetone, and Glass Sustainability 204

6.2   Further Implementation of Aluminum Heating Blocks for Energy Savings 206

6.2.1   Increasing Overall Usage of Energy Efficient Heating Methods 206

6.2.2   Data Collection and Interpretation 209

6.3   Concluding Remarks 212

6.4   References 214

6.4   Experimental Section 215

Supplemental Characterization 219

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	chemistry
Committee Chair / Thesis Advisor	Simon B. Blakey, Emory University
Committee Members	Frank E. McDonald, Emory University William M. Wuest, Emory University

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