Studies Towards the Synthesis of Malagasy Alkaloids, and Development and Applications of Regio- and Enantioselective Group IX Metal-Catalysed Reactions Public

Abstract

Part I of this dissertation describes efforts towards the synthesis of two monoterpenoid indole alkaloids – 11-demethoxymyrtoidine and myrtoidine. These alkaloids were isolated from Strychnos myrtoides and Strychnos mostuoides in the western regions of Africa and have been found to potentiate chloroquine activity against resistant strains of Plasmodium falciparum malaria. The core of these alkaloids was constructed using a previously developed iminium ion cascade annulation. A convergent strategy to install the EF dihydropyran/butyrolactone fragment of these alkaloids is discussed, as well as an alternate strategy involving a Semmelhack alkoxypalladation/carbonylation cascade reaction. Finally, studies towards the development of an enantioselective iminium ion cascade reaction using asymmetric ion-pairing catalysis are described.

Part II of this dissertation describes the development of regio- and enantioselective Rh- and Ir- catalysed allylic C–H functionalisation reactions and their application towards the synthesis of natural products containing non-canonical amino acid residues. Allylic C–H sulfamidation of allylbenzene derivatives is discussed, as well as the development of a new class of planar chiral rhodium indenyl catalysts for enantioselective allylic C–H amidation. DFT calculations indicate that allylic C–H activation of the olefin substrate is both rate- and enantiodetermining in this reaction, while C–N reductive elimination is regiodetermining, resulting from the electronic asymmetry imposed by the planar chiral indenyl ligand. Finally, the evolution of a synthetic route to darobactin A, a ribosomally-synthesised and post-translationally modified peptide with preliminary biological activity against Gram-negative bacteria, is described. 

Table of Contents

Table of Contents

Part I: Studies Towards the Synthesis of Malagasy Alkaloids Chapter 1. Introduction to the Malagasy Alkaloids

1.1 The Strychnos alkaloids 1

1.2 The Malagasy alkaloids 3

1.2.1 Structure 3

1.2.2 Biological activity 4

1.2.2.1 Chloroquine resistance to Plasmodium falciparum 4

1.2.2.2 Antimalarial activity of the Malagasy alkaloids 6

1.2.3 Prior synthetic studies 6

1.2.3.1 Synthesis of the malagashanol core (Canesi, 2020) 6

1.2.3.2 Synthesis of 11-demethoxy-16-epi-myrtoidine (Tang, 2016) 8

1.3 Conclusion 9

1.4 References 10

Chapter 2. Early Synthetic Studies Towards the Malagasy Alkaloids in the Blakey Lab

2.1 Pictet-Spengler cyclisations in indole alkaloid synthesis 13

2.2 Total synthesis of aspidophytine (Corey, 1999) 15

2.3 Iminium ion cascades to access the Malagasy alkaloids 16

2.3.1 Development of the cascade annulation to assemble the Malagasy core 16

2.3.2 Expanding the scope of the cascade reaction and total synthesis of malagashanine 17

2.3.3 Electronic tuning of the hemiaminal substrates controls the regioisomeric outcome of the cascade reaction 18

2.4 Prior studies towards the synthesis of 11-demethoxymyrtoidine 20

2.5 Conclusion 22

2.6 References 23

Chapter 3. Synthetic Studies Towards 11-Demethoxymyrtoidine and Myrtoidine

3.1 A convergent strategy towards 11-demethoxymyrtoidine and myrtoidine: installation of a pre-formed butyrolactone ring 26

3.1.1 Retrosynthetic plan 26

3.1.2 Synthesis of substrates for model systems 28

3.1.3 Synthesis of ketone 3.7 and kinetic enol triflate 3.6 29

3.1.3.1 Synthesis of Malagasy core 3.11 29

3.1.3.2 Oxidative cleavage of core structure 3.11 30

3.1.3.3 Synthesis of kinetic enol triflate 3.6 32

3.1.4 Forging the C15–C20 bond 33

3.1.4.1 Plan A – Stille coupling 33

3.1.4.2 Plan B – 1,2-addition to ketone 3.7 37

3.2 An alternate strategy to assemble the dihydropyran/furanone EF ring system – alkoxypalladation/carbonylation cascade reaction 41

3.3 Studies towards an enantioselective cascade annulation using asymmetric ion-pairing catalysis 44

3.3.1 Chiral anion-binding catalysis 45

3.3.2 Anion-binding catalysis 47

3.3.2.1 Prior work 47

3.3.2.2 Squaramides as anion-binding asymmetric ion-pairing catalysts 48

3.4 Conclusion 52

3.5 Experimental 53

3.6 Spectral data 75

3.7 References 94

Part II: Development and Applications of Regio- and Enantioselective Group IX Metal-Catalysed Reactions

Chapter 4. Introduction to Rh- and Ir-Catalysed Allylic C–H Functionalisation

4.1 Allylic C–H functionalisation via π-allyl complexes 99

4.2 Early contributions to RhCp*-catalysed allylic C–H amination 100

4.3 RhCp*-catalysed intermolecular allylic C–H functionalisation using external oxidants 101

4.3.1 Allylic C–N bond formation 101

4.3.2 Allylic C–O bond formation 103

4.3.3 Allylic C–C bond formation 103

4.3.4 Mechanistic investigations 106

4.4 Allylic C–H amidation via direct C–N reductive elimination from M(V) nitrenoid intermediates 107

4.4.1 RhCp*- and IrCp*-catalysed allylic C–H amidation 107

4.4.2 Mechanistic investigation 110

4.5 Conclusion 111

4.6 References 113

Chapter 5. Development of 2nd-Generation Regio- and Enantioselective Allylic C–H Functionalisation

5.1 Introduction 119

5.2 Development of alternate nitrenoid precursors for 2nd-generation allylic C–N bond formation 121

5.2.1 Survey of alternative electrophilic amines for allylic C–H amination 121

5.2.2 Development of allylic C–H sulfamidation using tosyl azide as a nitrenoid precursor 122

5.2.3 Scope and limitations of allylic C–H sulfamidation 123

5.3 A new planar chiral catalyst for regio- and enantioselective allylic C–H amidation 125

5.3.1 Overview of known chiral piano-stool cyclopentadienyl (Cp) complexes125

5.3.2 Introduction to the indenyl ligand 127

5.3.3 Catalyst preparation and development of enantioselective allylic C–H amidation (Dr. Caitlin Farr and Christopher Poff) 128

5.3.4 Scope and limitations of enantioselective allylic C–H amidation 130

5.3.5 Computational studies (Bohyun Park, Joongee Won, Kimberly Sharp) 133

5.4 Conclusion 135

5.5 Experimental 137

5.6 Spectral data 173

Chapter 6. Studies Towards the Total Synthesis of Darobactin A

6.1 Introduction 255

6.2 Darobactin A – structure and biology 257

6.3 Synthetic strategies towards related cyclophane macrocycle natural products 258

6.3.1 Synthesis of celogentin C 259

6.3.2 Synthesis of streptide 262

6.4 Evolution of synthetic strategy towards darobactin A 263

6.4.1 Initial approach – enantioselective allylic amidation/oxidative cleavage sequence 263

6.4.2 Revised approach – olefin carboamination 269

6.4.3 Current approach – iterative aminoquinoline-directed β C–H functionalisation of alanine 273

6.4.3.1 Amiquinoline-directed β C–H alkylation of amino acids 274

6.4.3.2 Model studies with phenylalanine 276

6.4.3.3 β C–H arylation with aryl iodide 6.77 277

6.5 Conclusion and future work 279

6.6 Experimental 280

6.7 Spectral data 289

6.8 References 300 

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Mot-clé	C–H Functionalisation Natural Product Synthesis
Committee Chair / Thesis Advisor	Simon B. Blakey, Emory University
Committee Members	Dennis C. Liotta, Emory University Frank E. McDonald, Emory University

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