Design, Synthesis, and Utility of Group IX Metal Catalysts for C–H Functionalization Open Access

Abstract

The field of group IX transition metal catalyzed enantioselective reaction development

has been dominated by complexes bearing C2-symmetric chiral cyclopentadienyl ligand

platforms. Key design elements within this ligand scaffold allow for logical modification

and effectively eliminate the need for catalyst resolution strategies once complexed.

However, the lengthy syntheses required for the best performing catalysts can limit

overall utility. Alternatively, the ligands used in catalysts featuring planar chirality are

often much simpler to synthesize but do require resolution strategies to access

enantioenriched pre-catalysts. Herein, we will describe our efforts towards the design and

synthesis of a planar chiral indenyl ligand scaffold, as well as the use of a simplified ligand

platform for enantioselective catalysis. Additionally, we will detail our efforts in the

development of new reaction methodology for natural product synthesis. This new

methodology uses a cobalt catalyst as we have endeavored to move into base metal

catalysis for more environmentally sustainable chemistry.

Table of Contents

Table of Contents

Chapter 1: Design and Synthesis of C2-Symmetric Chiral

Cyclopentadienyl Ligands and their Associated Late-Transition

Metal Complexes

1

1.1 Overview of C2-Symmetric Chiral Cyclopentadienyl Ligand Platforms

1

1.2 Synthetic Routes to Access Transition Metal Complexes Bearing C2-

Symmetric Cp Ligand Frameworks

3

1.2.1 Synthesis of Established C2-Symmetric Cp Ligands

3

1.2.2 Complexation of C2-Symmetric Ligands to Late-Transition

Metals

8

1.3 Selected Catalytic Studies Using C2-Symmetric Chiral Ligand Scaffolds

11

1.3.1 Group VIII Transition Metal Catalyzed Enantioselective

Transformations

11

1.3.2 Group IX Transition Metal Catalyzed Enantioselective

Transformations

11

1.4 Conclusion

15

1.5 References 16

Chapter 2. Planar Chiral π-Complexes: Assigning Planar Chirality,

Synthesis of Selected Ligands and their Associated Late-Transition

Metal Complexes, and Selected Catalytic Examples

20

2.1 Definition of Planar Chirality and Methods for Stereochemical

Assignment

20

2.1.1 Defining Planar Chirality 20

2.1.2 Assigning Planar Chirality of Transition Metal π-Complexes 21

2.2 Planar Chiral π-Complexes of Late Transition Metals 25

2.2.1 Synthesis of Ligands and the Associated Late-Transition Metal

π-Complexes for Selected Compounds

25

2.2.2 Selected Examples of Planar Chiral π-Complexes in

Enantioselective Catalysis

29

2.3 Conclusion

31

2.4 References 32

Chapter 3. Development of a Convergent Synthetic Route to

Improve Access to an Axial and Planar Chiral Indenyl Ligand

Scaffold

38

3.1 Introduction to the Baker-Type Ligand Scaffold

38

3.1.1 Examining the Reactivity Trends of Indenyl vs. Cyclopentadienyl

Ligands

38

3.1.2 Indene Ring Slip as a Key Facet of Asymmetric Induction

39

3.2 Development of a Modular Synthesis Towards a Baker-Type Ligand

Scaffold

40

3.2.1 Analysis of the Previously Disclosed Synthetic Route

40

3.2.2 New Modular Synthetic Route Development

43

3.3 Conclusion 46

3.4 References

48

3.5 Supporting Information

52

3.5.1 General Information

52

3.5.2 Experimental Section

53

3.5.3 Supplemental References

64

3.5.4 Spectra and HPLC Data

65

Chapter 4. Designing a Planar Chiral Rhodium Indenyl Catalyst for

Regio- and Enantioselective Allylic C–H Amidation

83

4.1 Introduction to Blakey Group Allylic C–H Functionalization

83

4.1.1 First Generation Racemic Allylic Amination and Etherification

83

4.1.2 Second Generation Oxidative Allylic C–H Functionalization

85

4.2 Design of a Planar Chiral Rhodium Indenyl Ligand Platform for

Enantioselective C–H Functionalization

86

4.2.1 From Model System to Active Catalyst

86

4.2.2 Stereochemical Determination of the Catalyst and Allylic Amide

Products

88

4.2.3 Reaction Scope

90

4.2.4 Mechanistic and Computational Studies

92

4.3 Conclusion

95

4.4 References

96

4.5 Supplementary Information

100

4.5.1 General Information

100

4.5.2 Experimental Section

101

4.5.3 Supplementary References 139

4.5.4 Spectra

140

Chapter 5. Towards a Peptide Macrocyclization Strategy via the

Cobalt-Catalyzed 1,2-Carboamidation of Acrylamides

166

5.1 Introduction to Ribosomally-Synthesized and Post-Translationally

Modified Peptides

166

5.1.1 Overview of Several Key Peptides Under Investigation by the

Blakey Group

166

5.1.2 Key Synthetic Strategies to Access RiPPs

167

5.2 Blakey Group Strategy to Access the Key -Amino Aryl-Alkyl

Disconnection

171

5.2.1 Application of Previous Methodology and New Synthetic Plan

171

5.2.2 Development and Optimization of the Cobalt-Catalyzed 1,2-

Carboamidation of Acrylamides

173

5.2.3 Tyrosine Hydroxamate Studies and Linear Peptide

Design/Synthesis

176

5.3 Conclusion

180

5.4 References

181

5.5 Supplementary Information

185

5.5.1 General Information

185

5.5.2 Experimental Section

186

5.5.3 Supplementary References

197

5.5.4 Spectra

199

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	Methodology Catalysis
Committee Chair / Thesis Advisor	Simon Blakey, Emory University
Committee Members	Huw Davies, Emory University Frank McDonald, Emory University

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