Total syntheses of haouamine A

In 2003, Zubia and coworkers elucidated the structures of haouamines A and B that were isolated from a marine tunicate species (Aplidium haouarianum) collected off the coast of southern Spain. Haouamine A was reported to have high activity against HT-29 human colon cancer cells (0.1 mug/mL), while haouamine B exhibited only mild cytotoxic activity. The unprecedented structure of these polyphenolic alkaloids is the result of an indeno-tetrahydropyridine core containing an all-carbon quaternary center onto which is fused the hallmark structural feature of these natural products: a 3-aza-[7]-paracyclophane macrocycle. A significant amount of strain is present within this macrocyclic system resulting in the bending of the cyclophane arene out of planarity into a boat-like conformation. These molecules were found to exist in solution as two rapidly interconverting isomers, and this was originally proposed by the isolation chemists to be a result of either atropisomerism of the cyclophane arene or slowed pyramidal inversion at nitrogen. Chapter 1 describes a first-generation racemic total synthesis of haouamine A that was enabled by the development of a cascade annulation sequence to build the indeno-tetrahydropyridine in one step from a readily available allyl oxime and the application of a pyrone/alkyne Diels-Alder reaction to access the paracyclophane. Chapter 2 describes synthetic investigations into the biosynthesis of these natural products. These resulted in the discovery of a mild, abnormal Chichibabin pyridine synthesis and the development of an enantioselective total synthesis of haouamine A. Furthermore, this led to a revised phenylalanine-based biosynthetic hypothesis. Chapter 3 describes a second-generation total synthesis of haouamine A that allowed for the production of large amounts (>0.5g) of the natural product. This approach involves the transfer of point-chirality to planar-chirality in a programmed synthesis of haouamine A and its atropisomer, proving through synthesis that the isomeric nature of these natural products is not due to atropisomerism. Biological testing of these compounds as well as a number of analogs has also been accomplished in PC3 human prostate cancer cells.