Date of Award
Master of Science (MS)
Tetrahydroisoquinolines (THI) are biologically active natural products with applications to a variety of diseases. These compounds also act as precursors for other pharmacologically active natural products. In this investigation, a new synthetic approach for generation of halogenated THIs was proposed. Using cross-linked tyrosinase aggregate, halogenated tyrosine and tyramine were oxidized to form halogenated catechols such as halogenated L-DOPA and dopamine. In a one-pot synthetic approach, the enzyme oxidation reaction was coupled to the Pictet-Spengler reaction, through the addition of an aldehyde, to generate halogenated THIs. The Pictet-Spengler reaction was catalyzed by the phosphate buffer in the reaction solution. The role of phosphate in the catalysis of the Pictet-Spengler reaction was also investigated. The rate of the Pictet-Spengler reaction between 3-hydroxyphenethylamine and propionaldehyde was found to be dependent on the concentration of monoprotic phosphate, indicating that the reaction is base catalyzed and specifically phosphate catalyzed. Through the use of a kinetic isotope experiment, the rate determining step was found to be the final, re-aromatization step of the reaction. The rate of this step was found to be dependent on one equivalence of the monoprotic phosphate species. An investigation of the role of phosphate in the regioselectivity of the Pictet-Spengler reaction also revealed that an increased concentration of the diprotic phosphate species resulted in a decrease in the formation of the ortho-cyclized isomer.
Fauser, Jordan Elise, "Enzyme-Mediated and Mechanistic Investigations of Tetrahydroisoquinoline Synthesis through the Pictet-Spengler Reaction" (2016). College of Science and Health Theses and Dissertations. 165.