Asymmetric Intramolecular C–H Aminations with Chiral-at-Ruthenium Complexes
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Philipps-Universität Marburg
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Chiral transition-metal catalysts in which the chirality only originates from a stereogenic metal center have attracted much attention in the past few years as their excellent catalytic performance has been illustrated through diverse applications in catalytic asymmetric reactions, especially enantioselective intramolecular C–H amination reactions. This thesis reports the synthesis of a series of newly modified chiral-at-metal ruthenium catalysts and their applications in challenging enantioselective intramolecular C–H amination reactions.
1) Synthesis of diverse ruthenium-based chiral catalysts with exclusive metal-centered chirality as a catalyst tool box was accomplished. Through modifications of the chelating carbene ligand, the catalyst’s property were changed, thus, behaved differently in catalytic asymmetric transformations. The newly modified ruthenium catalysts were used in different catalytic asymmetric intramolecular C–H amination reactions which are reported on chapter 2.1-2.4 of this thesis.
2) An catalytic enantioselective ring-closing C–H amination of 2-azidoacetamides was developed. A chiral-at-metal ruthenium complex served as the catalyst and provided chiral imidazolidin-4-ones in 31-95% yields, with enantioselectivities up to 95% ee, and catalyst loadings down to 0.1 mol% (740 TON). Mechanistic experiments reveal the importance of the amide group presumably by enabling an initial bidentate coordination of the 2-azidoacetamides to the catalyst (Chapter 2.1).
3) An application of a new class of chiral-at-metal ruthenium catalysts for enantioselective C-H amindations was developed. In the catalyst scaffold, ruthenium is cyclometalated by two 7-methyl-1,7-phenanthrolinium heterocycles, resulting in chelating pyridylidene remote N–heterocyclic carbene ligands (rNHCs). The non-C2-symmetric chiral-at-ruthenium complexes displayed unprecedented catalytic activity for the intramolecular C–H amidation of 1,4,2-dioxazol-5-ones and provided chiral lactams with up to 98% ee and catalyst loadings down to 0.005 mol% (up to 11200 TON), while the C2-symmetric diastereomer favored an undesired Curtius-type rearrangement. DFT calculations elucidated the origins of the superior C–H amidation reactivity displayed by the non-C2-symmetric catalysts compared to related C2-symmetric counterparts (Chapter 2.2) .
4) An enantioselective intramolecular C–H amination of N-benzoyloxyureas using a chiral-at-metal ruthenium catalyst was reported, providing chiral 2-imidazolidinones in yields of up to
99% and with up to 99% ee. Catalyst loadings down to 0.05 mol% were feasible. Control experiments were performed which support a stepwise nitrene insertion mechanism through hydrogen atom transfer of a ruthenium nitrenoid intermediate followed by a radical recombination. Chiral imidazolidines are prevalent in bioactive compounds and can be converted to chiral vicinal diamines in a single step. The synthetic value of the new method was demonstrated for the synthesis of intermediates of the drugs levamisole and dexamisole, the bisindole alkaloids topsentine D and spongotine A, and a chiral organocatalyst. (Chapter 2.3).
5) Chiral amino alcohols are important building blocks for the synthesis of drugs, natural products, chiral auxiliaries, chiral ligands and chiral organocatalysts. The catalytic asymmetric amination of alcohols offers a direct strategy to access this class of synthetic intermediates. In this part, we report a general intramolecular C–H nitrene insertion method for the synthesis of chiral oxazolidin-2-ones as precursors of chiral amino alcohols was developed. Specifically, the ring-closing C–H amination of N-benzoyloxycarbamates with just 2 mol% of a chiral ruthenium catalyst provided cyclic carbamates in up to 99% yield and with up to 99% ee. The method is applicable to benzylic, allylic, and propargylic C–H bonds and can even be applied to completely non-activated C–H bonds, although with somewhat reduced yields and stereoselectivities. The obtained cyclic carbamates can subsequently be hydrolyzed to obtain chiral amino alcohols. The method is highly practical as the catalyst can be easily synthesized in a gram scale and can be recycled after the reaction for further use. The synthetic value of the new method was demonstrated with the asymmetric synthesis of chiral oxazolidin-2-one as intermediate for the synthesis of the natural product (-)-aurantiolavine and chiral amino alcohols that are intermediates for the synthesis of chiral Box-ligand and the natural products hamacanthin A and dragmacidin A (Chapter 2.4).
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Created: 2020Issued: 2024-02-15Updated: 2024-02-15
Faculty
Fachbereich Chemie
Publisher
Philipps-Universität Marburg
Language
ger
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DoctoralThesis
DFG-subjects
Chiral-at-RutheniumAsymmetrische CH-Aminierung
DDC-Numbers
540
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Zhou, Zijun: Asymmetric Intramolecular C–H Aminations with Chiral-at-Ruthenium Complexes. : Philipps-Universität Marburg 2024-02-15. DOI: https://doi.org/10.17192/z2020.0540.
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This item has been published with the following license: In Copyright