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)
Abstract
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
3.2.2.1 Chemical Syntheses of Celogentin C 99
3.2.2.2 Chemical Synthesis of Streptide 105
3.2.2.3 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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