Mechanistic study of the oxidation of pteridine derivatives
Creators: name: Oyama, Kiyotaka
Publisher: name: University of British Columbia
Year: 2011

description: The permanganate oxidation of 6,7,8-trimethyllumazine (TML) (I, R = CH₃) was investigated and its mechanism was elucidated by means of kinetic and product studies. The oxidations of 6,7-diphenyl-8-methyllumazine (I, R = C₆H₅) with permanganate and of TML with potassium trans-1,2- diaminocyclohexanetetraacetatomanganate(III) (KMn[sup III]CyDTA, where CyDTA represents the ligand) were also studied, as an aid in understanding the oxidation process. [See Thesis for Diagram] It was found that permanganate oxidation of TML consists of a permanganate-independent path and permanganate-dependent path. The former is subject to general base catalysis by the phosphate buffer species above pH 3.5, with the rate being almost identical with that for the hydrogen-deuterium exchange reaction of the 7-methoyl group of TML multiplied by a factor of three. A kinetic isotope effect of 6.89 at 31.4° was obtained for TML deuterated at the 7-methyl group. From these results it was concluded that the initial step of the reaction is rate-determining removal of a proton by attack of general bases at the 7-methyl group to produce an enolate-anion. The mechanism of the subsequent steps was considered to be as follows; the enolate-anion undergoes an electron transfer rather than the addition reaction with permanganate, yielding a free radical intermediate, which reacts further with the permanganate to give a manganate ester intermediate. The latter decomposes via hydration at the 7-position to give formaldehyde and 6,8-dimethyl-7-oxolumazine. The permanganate-independent path below pH 3.5 is subject to general acid catalysis by hydronium ion as well as by the phosphate buffer species. The oxidation is somewhat faster than the exchange and a kinetic isotope effect of 2.46 at 31.4° was obtained for TML deuterated at the 7- methyl group. These facts were explained by assuming the presence of an hydration route as well as the enolization route. The permanganate-dependent path was found to be subject to specific acid catalysis and there was no kinetic isotope effect for the 7-CD₃ compound. Addition of permanganate to the carbon-carbon double bond at the 6,7-position of the protonated TML is suggested as the mechanism for the reaction. From the results obtained in the present study the utility of the oxidation method, which is frequently used to locate the site of hydration in heterocyclic systems, has been reexamined and additional limitations to those appearing in the literature regarding the method are suggested. Similarities between the reported enzymic conversion of 6,7-dimethyl- 8- ribityllumazine to 6-methyl-7-oxo-8-ribityllumazine and the oxidation of TML with KMn[sup III]CyDTA under aerobic conditions are pointed out. The mechanism of the latter was investigated and an autoxidation path initiated by electron transfer from the enolate-anion to KMn[sup III]CyDTA is proposed. During attempts to synthesize a model compound for flavin nucleotides, it was discovered that, methylation of 3-amino-2-methylaminopyridine with methyl iodide gives a product exclusively alkylated at the 3-amino nitrogen, rather than at the ring nitrogen as is found to be the case with most aminopyridines. The diversion of methylation from the ring nitrogen to the 3-amino nitrogen is attributed to a combination of steric and hydrogen bonding effects.