Oxidation of Tetrahydropyridines by MAO B Biomimetics: Mechanistic Studies

The Parkinsonian Syndrome-inducing effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the body have been well-documented since its discovery. However, its mechanism of oxidation by monoamine oxidase B (MAO B) has been debated for just as long. Proponents of the single electron transfer (SET) pathway of oxidation faced severe critiques in that the hypothesized radical intermediates arising from the SET pathway were never directly observed. Work performed herein provides that exact evidence using biomimetics of MAO B. The first section of the dissertation will highlight the ability of one such biomimetic, 3-methyllumiflavin (3MLF), to provide a chemical model for the oxidation of -unsaturated tetrahydropyridines. Using a nontoxic analog of MPTP, 1-methyl-4-(1-methyl-1-H-pyrrol-2-yl)-1,2,3,6-tetra-hydropyridine (MMTP), reactions with 3MLF were performed under both aerobic and anaerobic conditions. The anaerobic studies of these reactions proved to be the key to the direct observations (by 1H NMR and EPR) of flavin-derived radical behavior. Armed with the knowledge of how to prepare reactions for the direct observation of flavin radical intermediates, studies of N-cyclopropyl substrate derivatives were subsequently conducted to gather evidence for the formation of radical substrate intermediates. If the hypothesized SET is the first step of the reaction mechanism, then the resulting aminyl radical cation could undergo a cyclopropyl ring opening. Several products derived from the substrate were observed; among them were ring-opened variations suggesting that the reaction does begin with a SET. Thermodynamically, this process is unfavorable, leading to the hypothesis that this reaction step may be better described as a proton-coupled electron transfer (PCET). The kinetics of this process were studied at length. Finally, to provide a more compelling argument for the fundamental reactivities, two other flavin biomimetics are investigated. Their reactions with tetrahydropyridines were put under the same scrutiny as 3MLF, leading to the conclusion that the chemistry discussed herein is not unique to 3MLF, but is much more broadly applicable to other flavin biomimetics and MAO B.