Synthesis of piperidine and quinolizidine alkaloids

• Main Author: Nur Filza Mohamed Aslam
• Other Authors: Roderick Wayland Bates
• Format: Theses and Dissertations
• Language: English
• Published: 2017
• Subjects: DRNTU::Science::Chemistry::Organic chemistry::Organic synthesis
• Online Access: http://hdl.handle.net/10356/72719
• Institution: Nanyang Technological University

Natural products have been, and will continue to be, an important starting point for researchers in the quest for novel treatments for today’s ailments. While these molecules often have very highly potent or specialised activities, they may not be the perfect drug candidate. Medicinal chemists aim to improve their therapeutic activity and at the same time, maximise their physicochemical properties in order to deliver effective drug molecules. Our research has focused largely on the synthesis of natural products with application to medicinal chemistry. Herein is reported the use of N,O-heterocycles for the synthesis of structurally complex, biologically active molecules. Firstly, we report the use of isoxazolidines for the generation of 1,3-aminoalcohols which is an important functional moiety in substituted hydroxy piperidine and quinolizidine alkaloids. This approach has been applied to the synthesis of (-)-5-hydroxysedamine. This synthesis also features key approaches developed in our group, i.e. hydroformylation and diastereoselective dihydroxylation for the synthesis of piperidines. We believe our synthetic approach to be the most robust towards this natural product reported to date. In the following chapter, we sought to employ isoxazolidines to the synthesis of (+)-vertine, a macrocyclic quinolizidine alkaloid which was reported to possess antimalarial activity. Our approach would enable a facile and divergent method for the synthesis of vertine and other close analogues of the natural product. This would enable structure-activity relationship (SAR) studies to investigate the key pharmacophore needed for antimalarial activity. We initiated our studies with the synthesis of (-)-lasubine I, as a proof-of-concept to investigate the tractability of our synthetic strategy.