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Atroposelective Chiral-at-Rhodium Catalysis and Nitrene-Mediated Enantioselective Synthesis of Chiral α-Amino Acids with Ruthenium and Iron Catalysts
The interface of asymmetric and transition metal catalysis has greatly boosted the advancement of synthetic chemistry, especially in the context of an increasing demand of chiral organic molecules in various fields. In the past decade, our group developed a series of structurally unique chiral-at-me...
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| Format: | Dissertation |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2023
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| Online Zugang: | PDF-Volltext |
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| Zusammenfassung: | The interface of asymmetric and transition metal catalysis has greatly boosted the advancement of synthetic chemistry, especially in the context of an increasing demand of chiral organic molecules in various fields. In the past decade, our group developed a series of structurally unique chiral-at-metal complexes which have exhibited excellent catalytic reactivity and stereocontrol for catalyzing a series of asymmetric reactions. This thesis aims at exploring more application and tackling several previously unsolved challenges for employing such chiral-at-metal complexes in asymmetric catalysis.
Chapter 2. A catalytic protocol for the synthesis of axially chiral 2,5-disubstituted N-arylpyrroles is described. The method relies on the atroposelective alkylation at the C5-position of 2-monosubstituted N-arylpyrrole substrates by the electrophilic alkylating reagent N-acryloyl-1H-pyrazole. The bis-cyclometalated chiral-at-rhodium complex RhS serves as the chiral Lewis acid catalyst which is able to discriminate the interconvertible conformations of the starting materials. The reaction affords the products in up to 93 % yield and with up to >99.5 % e.e., using catalyst loadings that could be lowered to 0.05 mol%. The reaction is suitable of synthesizing structurally diverse N-arylpyrroles by the merits of excellent functional group tolerance and versatile transformations of acylpyrazole moiety. The reaction represents the first example of atroposelective reactions catalyzed by the bis-cyclometalated chiral-at-rhodium complexes.
Chapter 3. Regio- and stereoselectivity issues are often confronted in non-ring-closing asymmetric nitrene C(sp3)‒H insertion reactions. We present a strategy for addressing these issues by covalently connecting the nitrene precursor to the substrate (carboxylic acids). Upon metal-assisted cleavage of the connected nitrene precursor, both reaction fragments are bound to the metal catalyst, which allows the subsequent nitrene C‒H insertion to undergo via highly controlled cyclic transition states and to provide the acyclic amine products in excellent regio- and stereoselectivity. The reaction provides a surprisingly simple access for structurally diverse N-Troc-protected chiral α-amino acids with aryl, alkenyl and alkynyl side chains in up to 96% yield and with up to 99% e.e., from azanyl ester substrates that are
readily accessible by high-yielding carbodiimide-coupling of abundant carboxylic acids with V
N-Troc-protected hydroxylamines. The reaction represents the first example of highly regio- and stereocontrolled non-ring-closing nitrene C(sp3)–H insertion catalyzed by the C2-symmetric chiral-at-ruthenium complexes, as well as a breakthrough for the catalytic asymmetric synthesis of chiral α-amino acids.
Chapter 4. Intermolecular asymmetric nitrene C(sp3)–H insertion is a highly challenging research topic in nitrene chemistry, and to date most reported transformations suffer from low selectivity, inconvenient nitrene precursors, and/or extremely limited substrate scope. We explore an unprecedent mechanistic manifold for nitrene-mediated asymmetric intermolecular C(sp3)–H amination, namely directed nitrene C–H insertion by using deprotonated carboxylic acids as the directing group, which allows the formation of structurally defined cyclic transition states for the highly regioselective hydrogen atom abstraction and subsequent stereoselective C–N bond formation. The reaction is able to directly convert abundant feedstock carboxylic acids into highly valuable non-racemic chiral α-amino acids bearing aryl and alkyl side chains in up to 89% yield and with up to 97% e.e. The synthetic utility of this reaction is further enhanced by the use of carbamate protection groups such as Boc and Troc that are commonly employed in amino acid chemistry. This reaction represents the first example of directed intermolecular C(sp3)–H nitrene insertion and is a general protocol for the synthesis of chiral α-mono- and α,α-disubstituted α-amino acids. |
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| DOI: | 10.17192/z2023.0123 |