Discovery and development of novel dirhodium catalysts for selective intermolecular allylic C-H amination
Abstract/Contents
- Abstract
- Metal-catalyzed C--H functionalization has had an immense impact on streamlining synthesis by enabling previously inaccessible synthetic disconnections in organic synthesis and late-stage diversification of complex molecules. Dirhodium tetracarboxylate catalysts represent the state-of-the-art for intermolecular C(sp3)--H amination, but struggle to functionalize allylic sites due to the competitive reactivity of alkenes. Further advances in dirhodium-mediated C--H amination will require developing catalysts with enhanced stability and different ligand architectures to control selectivity in reactions with substrates bearing reactive functional groups and numerous C--H bonds. However, carboxylate ligands are inherently limited in their electronic, steric, and geometric tunability, which has severely hampered efforts to expand the scope of dirhodium-catalyzed C--H amination. To move beyond dirhodium tetracarboxylate catalysts, we developed a new, modular family of bridging ligands based on 2-pyridones. This work has advanced by capitalizing on a unique combination of computing tools, including molecular dynamics, transition state analysis, and statistical modeling, in a rationally connected feedback loop. These novel dirhodium catalysts mediate intermolecular allylic C−H amination with unprecedented selectivity. The most effective catalyst, Rh2(btz)3(O2CtBu), features one carboxylate and three substituted 2-pyridone ligands that create a spatially complex, conformationally dynamic reactive site. In addition to mediating high yielding amination reactions, these catalysts challenge the paradigm that rigid, well-defined ligand frameworks are optimal for controlling reaction outcomes. Our results demonstrate the versatility of 2-pyridone-derived ligands for optimizing catalyst performance. In addition, this work represents the first successful divergence from dirhodium tetracarboxylate complexes for catalyzing intermolecular C--H amination reactions. More broadly, our design blueprint showcases how data science and computational techniques can be implemented synergistically to help advance reaction design. By capitalizing on the efficiency of dirhodium-catalyzed intermolecular C--H amination reactions, we have developed a novel strategy for constructing saturated azacycles from readily available precursors. The preparation of substituted azetidines and larger ring, nitrogen-containing saturated heterocycles is enabled through efficient and selective intermolecular sp3-C--H amination of alkyl bromide derivatives. A range of substrates are demonstrated to undergo C--H amination and subsequent sulfamate alkylation in good to excellent yield. N-Phenoxysulfonyl-protected products can be unmasked under neutral or mild basic conditions to yield the corresponding cyclic secondary amines. The preparative convenience of this protocol is demonstrated through gram-scale and telescoped multistep procedures. Application of this technology is highlighted in a nine-step total synthesis of an unusual azetidine-containing natural product, penaresidin B.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Betz, Kerry Nicole |
|---|---|
| Degree supervisor | Du Bois, Justin |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Burns, Noah |
| Thesis advisor | Waymouth, Robert M |
| Degree committee member | Burns, Noah |
| Degree committee member | Waymouth, Robert M |
| Associated with | Stanford University, Department of Chemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Kerry N. Betz. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/vw246vc2555 |
Access conditions
- Copyright
- © 2022 by Kerry Nicole Betz
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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