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Catalytic N-demethylation of alkaloids with an Feᴵᴵᴵ-TAML macrocycle and syntheses towards new TAML analogues

thesis
posted on 22.02.2017 by Do Pham, Duy Dinh
The N-demethylation of specific tropane and opiate alkaloids enables the synthesis of various medicines. This thesis investigates the use of an iron(III) tetraamido macrocycle (Feᴵᴵᴵ-TAML) as a catalyst for the oxidative N-demethylation of tropane and opiate alkaloids with hydrogen peroxide as a green oxidant. The syntheses of new tetraamide macrocycles are also reported. Initial investigations examined the oxidative N-demethylation of tropane alkaloids to their nortropane derivatives with H₂O₂. After screening various reaction conditions with atropine, the optimised conditions were applied to preparative N-demethylation of atropine and scopolamine to noratropine and norscopolamine, respectively, in high conversion and good yields in a simple one-pot process without any chromatography. Some by-products were tentatively identified and putative N-demethylation reaction pathways were proposed. Further investigations conclusively identified N-formyl-noratropine and carbon-hydroxylated tropane derivatives as by-products of the catalytic reaction with atropine. Additional studies indicated that Feᴵᴵᴵ-TAML catalyses the oxidative N-demethylation of atropine to noratropine via a biomimetic pathway involving the formation and then decomposition of a N-hydroxymethyl-noratropine intermediate. Factors such as substrate concentration, alcohol co-solvent and oxidant structure, rate of oxidant addition and concentration of water were found to influence the selectivity of N-demethylation vs. N-methyl oxidation to N-formyl-noratropine, whereas temperature mainly affected conversion efficiency. It was found that Feᴵᴵᴵ-TAML also catalysed the N-demethylation of the opiate alkaloids thebaine and oxycodone but with much less selectivity. A set of new tetraamide macrocycles were synthesized to enable future studies on the effect of Feᴵᴵᴵ-TAML structure on reaction selectivity with tropane and opiate alkaloids. These syntheses were achieved by preparing the requisite malonyl dichloride precursors which were then cyclized with a common diamide diamine precursor. Bond rotation and ring inversion were observed for two of these macrocycles on the N.M.R. timescale and their associated thermodynamic activation parameters were measured. These studies showed that the activation energy for bond rotation of geminal substituents is predominantly influenced by the macrocycle ring structure rather than substituent size, while the activation energy for ring inversion is significantly influenced by substituent size. In addition, ring inversion appears to proceed via a more-ordered transition state, suggesting an associative solvent-mediated process.

History

Campus location

Australia

Principal supervisor

Milton Hearn

Year of Award

2015

Department, School or Centre

Chemistry

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Science

Exports