Multi-catalysis: Trifluoromethylation of Amides

https://tigerprints.clemson.edu/csrp/1020/thumbnail.jp

Asymmetric Lactone Synthesis via Hydroacylation and Stereoselective Cyclic Peptide Synthesis via Hydrogenation

Asymmetric transition metal catalysis has benefited human health by greatly facilitating access to natural products and therapeutic drugs. However, scientists continue to face challenges of developing more direct processes while minimizing the generation of unwanted wastes. As there is a high demand in the development of sustainable and atom-economical processes, the focus of my doctoral studies was to apply asymmetric catalysis in the development of conceptually unique and sustainable strategies for the synthesis of biologically important organic molecules. This dissertation includes: 1) the development of Rh-catalyzed enantioselective ketone hydroacylation as an atom-economical and general method for the synthesis of phthalide, 2) nickel catalyzed olefin hydroesterification for the synthesis of all-carbon quaternary stereocenters, and 3) a new synthetic strategy for preparing cyclic peptides using asymmetric hydrogenation.Ph.D.2015-12-18 00:00:0

Hydrogenation catalyst generates cyclic peptide stereocentres in sequence

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst-substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations

Enantioselective Intermolecular C–O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst

We report a series of enantioselective C–O bond cross-coupling reactions based on remote symmetry breaking processes in diarylmethine substrates. The key to the chemistry is multifunctional guanidinylated peptide-based ligands that allow highly selective, intermolecular Cu-catalyzed cross-coupling of phenolic nucleophiles. The scope of the process is explored, demonstrating efficiency for substrates with a range of electronic and steric perturbations to the nucleophile. Scope and limitations are also reported for variation of the diarylmethine. While the presence of an intervening <i>t</i>Bu group is found to be optimal for maximum enantioselectivity, several other substituents may also be present such that appreciable selectivity can be achieved, providing an uncommon level of scope for diarylmethine desymmetrizations. In addition, chemoselective reactions are possible when there are phenolic hydroxyl groups within substrates that contain a second reactive site, setting the stage for applications in diverse complex molecular settings

Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional Ligands: Desymmetrization of Diarylmethanes via Ullman Cross-Coupling

We report the development of a new class of guanidine-containing peptides as multifunctional ligands for transition-metal catalysis and its application in the remote desymmetrization of diarylmethanes via copper-catalyzed Ullman cross-coupling. Through design of these peptides, high levels of enantioinduction and good isolated yields were achieved in the long-range asymmetric cross-coupling (up to 93:7 er and 76% yield) between aryl bromides and malonates. Our mechanistic studies suggest that distal stereocontrol is achieved through a Cs-bridged interaction between the Lewis-basic <i>C</i>-terminal carboxylate of the peptides with the distal arene of the substrate

Stereodynamic Quinone–Hydroquinone Molecules That Enantiomerize at sp³‑Carbon via Redox-Interconversion

Since the discovery of molecular chirality, nonsuperimposable mirror-image organic molecules have been found to be essential across biological and chemical processes and increasingly in materials science. Generally, carbon centers containing four different substituents are configurationally stable, unless bonds to the stereogenic carbon atom are broken and re-formed. Herein, we describe sp³-stereogenic carbon-bearing molecules that dynamically isomerize, interconverting between enantiomers without cleavage of a constituent bond, nor through remote functional group migration. The stereodynamic molecules were designed to contain a pair of redox-active substituents, quinone and hydroquinone groups, which allow the enantiomerization to occur via redox-interconversion. In the presence of an enantiopure host, these molecules undergo a deracemization process that allows observation of enantiomerically enriched compounds. This work reveals a fundamentally distinct enantiomerization pathway available to chiral compounds, coupling redox-interconversion to chirality

Hydrogenation catalyst generates cyclic peptide stereocentres in sequence

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst-substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations