C-H Functionalization Inspired Total Synthesis and New Donor/Acceptor Carbenes for Asymmetric C-H Functionalization Public
Bosse, Aaron (Spring 2022)
Published
Abstract
Dirhodium(II)-catalyzed C-H insertion by donor/acceptor carbenes has become a powerful tool for catalyze controlled C-H functionalization. The Davies lab has spent decades developing various ligands to alter the steric and electronic profile of dirhodium tetracarboxylate catalyst, resulting in a “toolbox” of catalysts for a wide array of selective C-H functionalization reactions. The first chapter gives an overview of rhodium carbene chemistry, along with their applications in natural product synthesis.
The second chapter discusses the application of the newest generation of dirhodium tetracarboxylate catalysts applied to the total synthesis of (-)-cylindrocyclophane A. These C2-symmetric natural products have a fascinating molecular architecture featuring a [7.7]paracyclophane ring. I developed and accomplished a route encompassing 6 C-H functionalization steps and primarily constructing the carbon skeleton through these steps. Four enantioselective carbene-induced C-H functionalizations to generate the six stereogenic centers, two palladium-catalyzed C-H functionalizations of diazocarbonyl compounds, and four directed C-H acetoxylations. Currently I am on the final step in the synthesis where completion of this work will represent a pinnacle for what C-H functionalization can achieve in total synthesis.
The third chapter describes the successful completion of an enantioselective formal synthesis of (-)-aflatoxin B2. The route developed here highlights two impressive C-H functionalization methodologies enabling a completely novel strategy to this family of natural products. Chiral dirhodium-mediated C-H insertion not only establishes a key benzylic stereocenter with high enantioselectivity but also installs the appropriate functionality for the annulation of the C-ring. Following the carbene insertion, carbonyl-directed bis C-H acetoxylation site-selectively introduces the appropriate oxidation functionality needed. Together, these crucial transformations provide direct access to the tricyclic core of (-)-aflatoxin B2 and highlight the considerable potential of site-selective C−H functionalizations in natural product synthesis.
The fourth and final chapter details the development of a-aryl-a-diazoketones for highly selective intermolecular C-H functionalization. The inspiration for this work stems from the desire to expand the chemical space one can access with our rhodium carbene technology. We hypothesized the ketone functionality could function as a surrogate for chiral alcohols and amines, greatly expanding on the established work with aryl diazoacetates. Optimization of the ketone/catalyst pairing lead us to a highly selective system using an aryl ketone and Rh2(S-TPPTTL)4. Following functionalization, we demonstrated this new ketone handle can be used to synthesize chiral benzylamides, allowing access to new chemical space unseen by the previous diazoesters.
Table of Contents
Table of Contents
List of Figures
List of Schemes
List of Tables
List of Abbreviations
Chapter 1. Introduction to Selective C-H Functionalization via Dirhodium Carbenes and Applications in Total Synthesis.................……………………………………...…1
1.1. Site-selective C-H Functionalization …………………………….…….………….1
1.2. Dirhodium Carbene Chemistry and Catalyst Toolbox……………...……………..3
1.3. Applications of Dirhodium Carbene Chemistry in Total Synthesis……….………9
1.4. Conclusions…………………………………………………………………...….13
1.5. References………………………………………………………………..………14
Chapter 2. Streamlined Approach to (-)-Cylindrocyclophane A through C-H Functionalization Logic.………………………………………………………..……………......….19
2.1. Introduction to Cylindrocyclphanes……………………………………………...19
2.1.1. Isolation and Structure Determination……………………………………19
2.1.2. Biosynthesis of Cylindrocyclophane…….………..…………...…………21
2.1.3. Previous Total Syntheses of (-)-Cylindrocyclophane A………………….22
2.1.4. A C-H Functionalization Strategy to (-)-Cylindrocyclophane A…………26
2.2. Results and Discussion………..……………………………………………....….29
2.2.1. Model Synthesis of [7.7]Paracyclophane Core…………………………..29
2.2.2. Retrosynthetic Analysis ………………………………………………….37
2.2.3. Studies Toward the Synthesis of (-)-Cylindrocyclophane A……………..40
2.2.4. Third-Generation Retrosynthetic Analysis…………………..……….......52
2.2.5. Final Approach to (-)-Cylindrocyclophane A……………………....…….53
2.2.6. Endgame Strategies and Model Studies for Late-Stage Transformations…………………………………………………...……..58
2.3. Conclusions…………………………………………………………………...….62
2.4. Distribution of Credit……………………………………………………...……..63
2.5. References………………………………………………………………...……...64
Chapter 3. A C-H Functionalization Strategy Enables an Enantioselective Formal Synthesis of (-)-Aflatoxin B2…………………………………………………...….………......69
3.1. Introduction………………………………..…………….………………...……..69
3.1.1. Isolation, Structure Determination and Biosynthesis………………….…69
3.1.2. Previous Enantioselective Syntheses to (-)-Aflatoxin B2……………...…70
3.1.3. A C-H Functionalization Strategy to (-)-Aflatoxin B2……………………73
3.2. Results and Discussions………………………………..………………...............76
3.2.1. Enantioselective Primary C-H Insertion.....................................................76
3.2.2. Investigating a C-O Coupling Strategy.......................................................79
3.2.3. Completing the Enantioselective Formal Synthesis...................................80
3.3. Conclusions………………………………………………………….……...……81
3.4. Distribution of Credit…………………………………………………………….82
3.5. References…………………………………………………………..….…...……83
Chapter 4. Aryl Diazoketones as New Donor/acceptor Carbene Precursors for Highly Selective Intermolecular C-H Functionalization Reactions....................................86
4.1. Introduction………………………………………………………..….……...…..86
4.2. Results and Discussions……………………......…………………..….......…..…92
4.2.1. Catalyst Screen and Reaction Optimization……………………………...92
4.2.2. Aryl Diazoketone Scope ………………..…….…………………...…......96
4.2.3. Substrate Scope………………………………….………………..…….100
4.2.4. Derivatization of Aryl Diazoketones Products……..…………….……..107
4.3. Conclusions…………………………………..…………………….…………...110
4.4. Distribution of Credit……………………………………………………...……111
4.5. References……………………………………....………………………………112
Experimental Section……….....……………………………....………………………...…….116
5.1. General considerations……………………………….....………………………….116
5.2. Experimental Section for Chapter 2………………………….…………………..…117
5.3. Experimental Section for Chapter 3……………………………………………...…150
5.4. Experimental Section for Chapter 4…………….………………………………..…163
Appendix…………….....…….………………………....………………………………..…….200
NMR Spectra.……….....……………………………....……………………………..…201
HPLC Data…….....……………………………....………………………………..……284
X-Ray Crystallographic Data……………………….......................................................314
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