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Title: Cobalt-Catalyzed Alkene Asymmetric Hydrogenation
Authors: Friedfeld, Max
Advisors: Chirik, Paul J
Contributors: Chemistry Department
Subjects: Chemistry
Issue Date: 2016
Publisher: Princeton, NJ : Princeton University
Abstract: The asymmetric hydrogenation of alkenes has been of long-standing interest as a direct route to single-enantiomer small molecules used as pharmaceutical drugs, agrochemicals, and natural products. Developing base-metal catalysts based on cobalt that can accomplish this transformation is of considerable interest in lowering manufacturing costs and discovering new chemistry and reaction mechanisms. The mechanistic chemistry of C1-symmetric pyridine-diimine cobalt alkyl pre-catalysts in the hydrogenation of α-isopropylstyrene was initially explored. The catalyst resting state, (S)-CoH, was identified using 1H-NMR spectroscopy and X-ray diffraction studies. Stoichiometric and catalytic experiments revealed that 2,1-alkene insertion is fast and reversible and 1,2-alkene insertion is rate-limiting and enantiodetermining. The pre-catalyst, (S)-CoCH3, can accomplish the enantioselective hydrogenation of 3-aryl-indenes and 1-aryl-dialins. In exocyclic di-substituted alkenes, control of relative rates of hydrogenation and isomerization is important in achieving high levels of enantioselectivity. A combination of initial turnover experiments and catalytic deuteration experiments support this rationale. Achiral bisphosphine cobalt dialkyl pre-catalysts of the form (P2)Co(CH2SiMe3)2, P2 = achiral bidentate phosphine, were also examined. In the hydrogenation of hydroxyl-containing substrates, the presence of a proximal hydroxyl-group was found to greatly increase the reactivity of the catalysts for the hydrogenation of alkenes. A cobalt(0) complex dppeCoCOD (dppe = 1,2-diphenylphosphinoethane, COD = 1,5-cyclooctadiene) was isolated from a catalytic reaction. High-throughput experimentation was used to evaluate various catalyst parameters, resulting in discovery of catalysts for the highly enantioselective hydrogenation of dehydroamino acid derivatives, α-acetamidostyrene, and trans-methylstilbene. Various cobalt(II) salts were identified that in combination with chiral phosphine ligands and an organometallic additive furnished highly active pre-catalysts in the hydrogenation of methyl 2-acetamidoacrylate (MAA). Further optimization revealed that this hydrogenation could be accomplished using methanol solvent. The synthesis of Co(II) aryloxide and alkoxide derivatives were accomplished and these complexes were active in the hydrogenation of MAA. Cobalt(I) and cobalt(0) complexes were also synthesized and were active pre-catalysts in the hydrogenation of MAA in methanol. These cobalt pre-catalysts were next used in the synthesis of levetiracetam, an anti-epilepsy drug. Various parameters such as ligand, cobalt source, additive, solvent, and temperature, were optimized to develop highly active and enantioselective cobalt pre-catalyst combinations in the synthesis of levetiracetam.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog:
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

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