Asymmetric synthesis of tetrahydroquinolines via aza-Michael reactions

Abstract

The tetrahydroquinolines structural unit is found in a number of natural products that exhibit a variety of biological activities including anti-allergic, anti-inflammatory and antitumour. As a result there is significant interest in their synthesis. This PhD thesis describes the work undertaken in the development of a new synthetic route that can be applied to the asymmetric synthesis of structurally diverse tetrahydroquinolines. The introductory chapter outlines the main current synthetic strategies towards tetrahydroquinolines and their application to the synthesis of some biologically interesting compounds. Chapter 2 discusses work on the total asymmetric synthesis of the Galipea alkaloids. An aza-Michael reaction was used to install the required stereochemistry. Extensive optimisation of the aza-Michael reaction resulted in high enantioselectivities, with optically pure material obtained upon recrystallisation. Various synthetic procedures were investigated for formation of the tetrahydroquinoline ring system and the remainder of the synthesis, with the Galipea alkaloids obtained from a common precursor. Work towards the formal synthesis of the Martinelline alkaloids, using the aza-Michael reaction to set the first stereocentre, is detailed in Chapter 3. A range of different α, β-unsaturated carbonyl and anilines were investigated for the aza-Michael reaction, with 85% enantioselectivity obtained on optimisation. Formation of the tetrahydroquinoline core was achieved and the installation of the second chiral centre investigated. Chapter 4 describes any miscellaneous work conducted, including preliminary investigations towards the synthesis of levonantradol. The last Chapter contains the experimental procedures and characterisation data for all the compounds synthesised during the course of this project.