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The Development of a Recyclable Molybdenum Dearomatization Agent

Myers, Jeffery
Format
Thesis/Dissertation; Online
Author
Myers, Jeffery
Advisor
Harman, Walter
Abstract
Molecular libraries are largely made up of unsaturated, “flat” molecules. These planar, achiral molecules do not provide the complexity that medicinal chemists need to fully investigate the importance of molecular topology in the design and development of successful drug candidates. For this reason, functionalized alicyclic molecules are inherently more advantageous than their planar analogues because they contain potential stereocenters. Arenes represent a wealth of opportunities as synthons for functionalized alicyclic molecules because of their abundance in nature, their stability, and the diversity of substituents present. Being unsaturated, aromatic molecules offer numerous locations for addition and thus the functionalization and creation of stereocenters can, in theory, easily be achieved. Traditional methods for creating alicyclic molecules from aromatics include the Birch reduction, photocycloaddition, and enzymatic oxidation. However, perhaps the greatest potential lies in the ability to complete these transformations using transition metals. Transition metal fragments such as {Cr(CO)3}, {Mn(CO)3}+, and {FeCp}+ can activate aromatics through an electron-withdrawing, η6-coordination that makes the arene susceptible to nucleophilic attack. Although this method can yield alicyclic molecules, it more commonly results in the creation of substituted aromatics. A complementary strategy to this use of these electron-poor transition metals lies in the activation of aromatic molecules through η2-coordination to an electron-rich metal complex. This coordination is controlled by the donation from a dπ orbital of the metal into a π* orbital of the aromatic ligand. This donation results in a disruption of the aromaticity (e.g., dearomatization) making the ligand susceptible to tandem electrophilic-nucleophilic additions. Utilizing this dearomatization method, the stepwise, controlled synthesis of functionalized alicyclic compounds directly from aromatic molecules can be achieved. The use of electron-rich transition metals in the disruption of aromaticity has been investigated over the past three decades with the following metals: osmium (II), rhenium (I), tungsten (0), and less so with molybdenum (0). This project seeks to develop a dearomatization agent that contains all of the advantages of the previous three decades worth of exploration into one metal scaffold, {TpMo(NO)(L)}. In this vein, we have demonstrated the ability to bind a variety of aromatics by a reduction of TpMo(NO)(L)(I) (where L = N-methylimidazole (MeIm) or N,N-dimethylaminopyridine (DMAP)) in the presence of the desired coordinating ligand (Lπ). This air-stable iodo complex can be synthesized on a large scale (> 150 g) without chromatography. Coordination complexes of certain aromatic molecules can be isolated from the reduction of this iodo precursor in the presence of the desired ligand on scales up to 13 g. Once bound, the dearomatized ligands are activated toward organic transformations, which, after oxidative decomplexation, yield novel small molecules. Oxidative decomplexation of the modified organic ligand can be accomplished with a mild oxidant (e.g., air) or with iodine to recover the TpMo(NO)(L)(I) complex. The novel organics isolated during this research have been submitted for screening through Eli-Lilly’s Open Innovation Drug Discovery Program.
Language
English
Published
University of Virginia, Department of Chemistry, PHD (Doctor of Philosophy), 2017
Published Date
2017-04-06
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
Creative Commons Attribution LicenseCreative Commons Attribution License
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