Deprotonation–Substitution of N-Boc-tetrahydroisoquinolines

Abstract Tetrahydroisoquinolines (THIQs) are found in a wide range of natural products and compounds with biological activity. This thesis describes the methodology of deprotonation‒substitution as an efficient route to 1-substituted THIQs and 3-substituted THIQs. This methodology was developed by using organolithium and organomagnesium chemistry. Firstly, methods were developed for the lithiation–substitution of tetrahydroisoquinolines by carrying out in situ ReactIR spectroscopic monitoring of deprotonation reactions. Moderate to high yields of products were obtained under the optimum reaction conditions. The lithiation‒substitutions of tetrahydroisoquinolines A were carried out. This chemistry was applied to a short synthesis of the alkaloids (±)-dysoxyline and (±)-crispine A. The lithiation–substitution of N-Boc-3-phenyltetrahydroisoquinoline B was also investigated. Lithiation was found to occur with approximately a 2:1 ratio at C-1 to C-3. NMR studies and DFT analysis were carried out in order to calculate the ratio of the two rotamers of B. Investigations have also focused on N-Boc-3-cyanotetrahydroisoquinoline and N-Boc-2-cyanopyrrolidine. High enantioselectivities of the forming products could be obtained from the sequence of deprotonation–substitution of these compounds at –104 ºC using magnesium bases. Altering the solvent was shown to have a large impact on the yield and enantioselectivity of the products.