Lucilactaene, a cytotoxic natural product isolated from the fungi of the genus Fusarium in 2001 by Osada and co-workers, was found to arrest cell cycle in a p-53 independent manner, specifically in cells possessing a temperature-sensitive p53 protein. The interesting structure of lucilactaene, with its lactam nucleus and polyunsaturated side chain, as well as its unique biological activity made it an attractive target for synthesis. The total synthesis of lucilactaene has recently been accomplished in eight linear steps, using a highly convergent strategy. This convergency was accomplished by a three-step metal cross-coupling sequence utilizing cuprate, Stille, and Suzuki-Miyaura couplings. Interestingly, lucilactaene is structurally related to a variety of Fusarium metabolites, but their reported biological is extremely diverse, and based on such minor architectural variations, investigations have begun into the structural origin of their biological activity.
Ceratamines A and B, naturally occurring antimitotic agents, were isolated from the marine sponge Pseudoceratina sp., collected in Papua New Guinea. These marine natural products arrest cell cycle at mitosis and stimulate microtubule polymerization in the absence of normally associated proteins. Due to their potential as novel anti-cancer drugs, these structurally simple types of compounds containing no chiral centers have attracted considerable attention.
Efficient construction of the ceratamines relies, on focusing primarily on a highly effective synthesis of the imidazo[4,5-d]azepine heterocyclic core. A strategy was developed, which relied on a late stage introduction of the fused 2-aminoimidazole ring via a readily available alpha-bromoketone. Unfortunately, the key reaction did not construct the 2-aminoimidazole ring system, and instead underwent a Favorskii rearrangement. The events leading up to this rearrangement, its discovery by X-ray crystallography, and the mechanistic rational behind the Favorskii rearrangement will be discussed. Current work resides on an alternate strategy, using an alpha aminoketone to effect fusion of the desired imidazole ring system. By synthetically accessing these natural products in a convergent manner, a framework for diversification is created, allowing for the ability to build large libraries of compounds; establishing their potential in cancer chemotherapeutics.