Abstract by Sebastian Clementson

The chemical complexity and inherent biological activities of natural products have inspired drug discovery for decades. This thesis describes the total synthesis of Erythrina natural products in the pursuit of novel nicotinic acetylcholine receptor (nAChR) antagonists. The major objective was to pursue a concise synthesis of the Erythrina scaffold that would allow entry into several sub-categories of this alkaloid family. This goal was achieved and a unifying approach to aromatic and lactonic Erythrina alkaloids is described herein. Emphasis was placed on developing a synthesis that would permit late stage diversification of the Erythrina scaffold in order to study the interactions of these alkaloids with the target receptor. Consequently, a common intermediate from the total synthesis route was utilized as a platform, upon which over 25 natural product analogues were synthesized. Pharmacological profiling of these target compounds revealed that a clear majority of them had potent antagonistic properties in functional- and binding-assays alike. Several subclasses of natural and unnatural Erythrina alkaloids were accessed, some of which outcompeted known potent compounds of this natural product family.