Catalytic asymmetric cyclization reactions of chiral cyclopentadienylruthenium and indenylruthenium complexes
Abstract/Contents
- Abstract
- Using transition metal catalysis to rapidly increase complexity for the construction of small molecules has been one of the most important areas of research in the field of synthetic organic chemistry. In particular, cyclopentadienylruthenium (CpRu) catalysis has previously been shown by our research group and others to be a selective, cost-effective, and atom-economical means of achieving this goal. In an effort to extend CpRu catalysis to enantioselective variants of these reactions, our group had previously developed CpRu complexes containing tethered chiral sulfoxides for their successful application towards asymmetric allylic substitution reactions. This work describes our efforts to expand the chemistry of these CpRu-sulfoxide complexes and to synthesize novel chiral CpRu and indenylruthenium (IndRu) catalysts for the discovery of new catalytic asymmetric cyclization reactions. CpRu-sulfoxide complexes were used to perform an asymmetric redox bicycloisomerization reaction that constructed [3.1.0] and [4.1.0] bicycles from propargyl alcohols. Initial reaction optimization was performed on 1,7-enynes due to the products' similarity to known triple-reuptake inhibitor GSK1360707. CpRu complex containing a tethered para-methoxy sulfoxide ligand proved to be the optimal catalyst for this reaction. Variation of the 1,7-enyne substrate structure revealed that a bulky 2,4,6-triisopropylbenzenesulfonyl (Tris) protecting group on the nitrogen-containing backbone was essential for observing high enantioselectivities for [4.1.0] bicycles. While THF proved to be the optimal solvent for redox isomerization of [4.1.0] bicycles, acetone provided the best results for [3.1.0] bicycles. Enantiomeric ratios as high as 98.5:1.5 were observed with Tris-containing [3.1.0] bicycles. The chemistry could be extended to 1,6-enynes containing other substrate tethers, including tosyl, diphenyl phosphoramidate, and dibenzyl malonate tethers. Nitrogen protecting groups were shown to be removable under reducing conditions. Catalysis performed with enantiomerically enriched propargyl alcohols revealed a matched/mismatched effect that was strongly dependent on the nature of the solvent. To the best of our knowledge, this methodology was the first example of a ruthenium-catalyzed asymmetric cycloisomerization reaction. Unfortunately, CpRu-sulfoxide complexes were shown to be inefficient and poorly selective catalysts for the enyne cycloisomerization and redox isomerization/C-H insertion reactions. We hypothesized that either the bound sulfoxide ligand was too electron-rich or that the catalyst had an insufficient number of coordination sites available for catalysis. In order to test our hypothesis, we synthesized CpRu complexes that contained more electron-withdrawing S-chiral ligands. While chiral sulfimide- and sulfinamide-containing complexes could promote enyne cycloisomerization, these catalysts were poorly enantioselective. These results led us to believe that the ligands were too weakly ligated to the metal center and decomplexed under the reaction conditions. Novel coordinatively unsaturated chiral indenylruthenium complexes with a tethered chiral sulfoxide were designed and synthesized. Enantiomeric ratios of up to 75:25 for enyne cycloisomerization and 84:16 for enyne hydroxycyclization could be obtained using these catalysts. When applied to the asymmetric redox isomerization/C-H insertion reaction, chiral indenylruthenium complexes could promote this reaction in up to 90:10 e.r.. The main disadvantage of using these tethered complexes is that they are not commercially available and must be made through multistep syntheses. We discovered that commercially available catalyst CpRu(MeCN)3PF6, when used in conjunction with a chiral phosphoramidite ligand, can perform an asymmetric interrupted metallo-ene reaction of (E)-allylic chlorides in excellent enantioselectivity. To our knowledge, this represents the first example of using CpRu-phosphoramidite complexes for a catalytic asymmetric transformation. The C1-symmetry and 3,3'-substitution on the BINOL-based phosphoramidite were key to the high levels of enantioinduction observed. Carbocyclic and heterocyclic 5- and 6-membered rings could be constructed in > 20:1 d.r. and up to 99:1 e.r.. As a demonstration of the utility of this methodology, diastereoselective Friedel-Crafts reactions were performed on the chiral benzylic alcohol products that were observed to proceed with retention of configuration.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Ryan, Michael Christian |
|---|---|
| Associated with | Stanford University, Department of Chemistry. |
| Primary advisor | Trost, Barry M |
| Thesis advisor | Trost, Barry M |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Waymouth, Robert M |
| Advisor | Du Bois, Justin |
| Advisor | Waymouth, Robert M |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Michael Christian Ryan. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Michael Christian Ryan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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