Total Synthesis of Zoanthenol

The aim of this postdoctoral research project is to develop the first total synthesis of Zoanthenol a complex natural product in a stereoselective and efficient way. Zoanthenol belongs to the zoanthamine alkaloids, heptacyclic marine alkaloids isolated from marine zoanthids, which have attracted much attention due to their interesting biological and pharmaceutical properties and beautiful chemical structure with high stereochemical complexity. Zoanthenol showed antiplatelet activity and acted as highly selective inhibitors in the present of collagen but showed no activity in the presents of arachidonic acid and thrombin. This selective activity is extremely important in the treatment of cardiovascular diseases, as this will result in only a small change in haemostasis and therefore providing a saver drug. With seven rings and nine stereocenters confined to a C30 framework, Zoanthenol is a densely functionalized, architecturally complex molecule. The greatest synthetic challenge lies in the C ring with its five contiguous stereocenters, three of them quaternary. Therefore a major focus will be on the stereoselective formation of the ABC ring system as previous work proved that the complicated hemi-aminals forming the DEFG rings are thermodynamically favored. This proposal outlines a unique total synthesis of the target molecule. In a highly convergent route the molecule is dissected into three relatively equally complex building blocks. The key steps consist of the fragment coupling by diastereoselective Grignard addition, a conjugated addition to build up the ABC ring system and a Horner- Wadsworth-Emmons reaction to attach the southern part and build up the overall carbon-skeleton. The crucial C ring will be constructed by Diels-Alder addition which should generate two of the required quaternary stereocenters in one step. As this kind of DA reaction has not been performed before and can be considered risky, an alternative route with higher flexibility is additionally outlined. An aryl annulation will generate the AB ring system and the C ring will be annulated stepwise, a 1,4-addition and alkylation sequence will install the two vicinal quaternary stereocenters and the southern part will be attached at a late stage by an alkyne addition to an aldehyde. This total synthesis will present only the second total synthesis of one of the members of this interesting and highly complex class of natural products.