The Development of Planar Chiral Indenyl Catalysts and the Progress Towards Synthesis of the Western Macrocycle of Darobactin A Open Access

Laws, David (Summer 2023)

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Planar chiral catalysis has been growing in both popularity and relative usefulness over the last two decades. However, synthesizing and resolving these catalysts remains a challenge. The first half of this dissertation will address efforts to provide a streamlined enantioselective synthesis of indenyl planar chiral catalysts, as well as more targeted catalyst development in the context of planar chiral indenyl complexes to improve utility in a variety of reaction profiles. Secondly, we will pivot to the area of ribosomally synthesized and post-translationally modified peptides. These natural products contain unique and valuable bioactivity profiles, but the post translational modifications also render them difficult to provide via chemical synthesis. In the second half of this dissertation, we will explore a novel approach towards the synthesis of darobactin A and its western macrocycle.

Table of Contents

Chapter 1. Synthesis, Chiral Resolution and Activity of Late-Transition Metal Planar Chiral Complexes                                                                                                            1

1.1    The Synthesis and Resolution of Late-Transition Metal Planar Chiral Complexes                                                                                         1                                                                                      

1.2    The Catalytic Activity of Late-Transition Metal Planar Chiral Complexes in Enantioselective Transformations                                                                                   11

1.3    Conclusions                                                                                   16

1.4    References                                                                                   18

Chapter 2. Progress towards the Enantioselective Synthesis of Planar Chiral Indenyl Complexes and Design of Planar Chiral Rh(III) Indenyl Catalysts                                                                                                       22

2.1    Recent Advances in Rh and Ir Catalyzed Allylic C–H Functionalization         22

2.2    The Development of the Blakey Indenyl Catalyst         27

    2.2.1 Mechanistic Insight into Allylic C–H Functionalization Using External Oxidants    27

    2.2.2 Development of the Blakey Indenyl Catalyst    30

2.3    Enantioselective Synthesis of Planar Chiral Rhodium Catalysts         33

2.3.1  Synthesis 34

2.3.2  Conclusions 36

2.4    Exploration of Electronic Effects in the Planar Chiral Indenyl Scaffold         37

2.4.1  Synthesis and Reactivity         39

2.4.2  Conclusions 42

2.5     Experimental Details         43

2.6    Spectral Data         55

2.7    References         85

Chapter 3. Ribosomally Synthesized and Post-translationally Modified Peptides containing C–O and C–C Crosslinks                                                                                                         93

3.1    The Generic Biosynthesis of Ribosomally Synthesized and Post-Translationally modified Peptides                                                                                   93

3.2    Chemical Synthetic Approaches towards Ribosomally Synthesized and Post-translationally Modified Peptides containing C–O and C–C Crosslinks                                                                                    95

3.2.1  Synthetic Approaches towards forging Alkyl-Aryl C–O Crosslinks in RiPPs                  96

3.2.2  Synthetic Approaches towards RiPPs with C–C Crosslinks containing Tryptophan                  99
 Chemical Syntheses of Celogentin C         99
 Chemical Synthesis of Streptide         105
 Chemical Synthesis of Tryptorubin A          106

3.2.3  Chemical Syntheses of Darobactin A         109

3.3    Conclusions         113

3.4    References                       115

Chapter 4. Progress Towards the Synthesis of the Western Macrocycle of Darobactin A                                                                                                               119

4.1    Synthetic Strategy towards the Total Synthesis of the Western Macrocycle of Darobactin A         119

4.2    Synthesis of Amino Acid Fragments         122

4.2.1  Synthesis of 7-substituted Tryptophan Derivatives         122

4.2.2  Synthesis of erythro-hydroxy-L-Tryptophan         124

4.2.3  Synthesis of threo-hydroxy-L-Tryptophan         127

4.3    Exploration of C–O Crosslinking Methods         128

4.4    Conclusions         133

4.5    Experimental Details         135

4.6    Spectral Data         152

4.7    References         175

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