Total synthesis of Providencin and Bielschowskysin

The aim of this project is the first total synthesis of the unusual and highly complex diterpene furanocembranolide providencin. This compound has some novel structural features such as a highly substituted cyclobutane and two epoxides on the carbocyclic ring. Moreover the ring strain of the macrocyclic system appears relatively high. The synthesis envisages a ring closure via metathesis reaction after which the furan ring shall be closed from a 1,4- diketone. The second part of the project refers to a possible biosynthetic connection between providencin and a related diterpene bielschowskysin which has been isolated from the same gorgonian species. Specifically a novel Baeyer- Villiger oxidation of the cyclobutane ring should initiate a peroxide attack on the furan ring and create a double bond suitable for a [2+2]-photocyclization to form the characteristic cyclobutane cage structure of bielschowskysin. In addition to this biomimetic synthesis a more conventional synthesis of bielschowskysin is also suggested. Once the synthesis is completed the biological activities of the compounds as antitumor agents or antibiotics will be tested.

Due to their rich functionalization and diverse biological activities marine furanocembranolides have received enormous attention over the past few years. Structurally, these secondary metabolites feature a 12- or 14-membered carbocyclic framework with varying degrees of oxygenation, into which a substituted furan ring and a ?-lactone subunit are embedded. Quite recently, small quantities of another member of this class, called providencin and bielschowskysin, have been isolated by the Rodriguez group from the seaplume Pseudopterogorgia kallos, collected in the Southwestern Carribean Sea near Providencia Island. providencin was shown to exhibit The new natural products were found to express high levels in vitro anticancer activity and might serve as possible lead structures for drug development. Also, the structural features of providencin and bielschowskysin are unique and these natural products represent an interesting synthetic targets. Goal of the project was the synthesis of these fascinating molecules. Despite the interesting features of these natural products, only few research groups are actively working in this research field.During the course of the project, several different approaches for the construction of macrocycle as well as two different synthesis of the cyclobutane moiety have been developed. Several segments have been prepared to allow optimization of the macrocyclization.During the time span of the project, substantial progress has been made toward the synthesis of providencin. Experience gained during the course of the project has been incorporated in the development of synthetic approaches towards related natural products of similar biological importance.