Biomimetic Total Synthesis of Elisabethin A

Elisabethin A is a marine diterpenoid isolated from West Indian Sea Whip Pseudopterogorgia elisabethae. The carbon framework and relative stereochemistry of elisabethin A were assigned on the basis of exhaustive spectroscopic studies and X-ray diffraction which did not allow to establish the absolute configuration of the natural compound. The complex tricyclic cis,trans-fused 5,6,6 ring system of elisabethin A together with fully substituted enedione functionality and six contiguous stereogenic centers present considerable challenge for total synthesis. Since only very small quantities of elisabethin A were isolated from natural sources and no total synthesis is available so far, pharmacological activities of this compound have not been investigated until now. However, many members of this family display substantial biological activity as anti-inflammatory, anticancer, antitubercular, and antibacterial agents and thus it is very likely that elisabethin A will also exhibit some of these. The goal of this project is the biomimetic total synthesis of elisabethin A which should allow the preparation of enough material for detailed investigation of its biological activity and should approve the absolute configuration as well as its biogenesis (biosynthesis).

Due to their rich functionalization and diverse biological activities marine terpenoids have received enormous attention in both isolation chemistry and total synthesis. One ample source of these compounds is the West Indian octocoral fauna, most notably the gorgonian corals (also known as sea whips, sea fans or sea plumes), of which near two hundred species are known. The by far largest portion of novel natural products isolated from this source is diterpenoids. A. D. Rodrguez stated in 1995 that over two hundred metabolites have been reported between 1985 and 1994, yet only approximately 20% of all octocorals have been investigated. A more recent review from 2008 described additional six hundred compounds possessing one of 40 carbon skeletons. This enormous wealth in structure and functionality attracted many total synthetic chemists. One of the diterpenoids yet to surrender to total synthesis is elisabethin A. It was isolated in 1998 by Rodrguez and co-workers from Pseudopterogorgia elisabethae. The structure was elucidated from exhaustive spectroscopical analysis, high resolution MS. The postulated structure was then confirmed by means of X-ray diffraction analysis. Yet it has to be noted that the absolute stereochemistry could not be pinpointed. Since only 25 mg of elisabethin A were isolated, testing for biological activity was very limited. However other members of the elisabethin family show significant antitumor and antituberculosis activity, which is another incentive to tackle the synthetic challenges posed by this complex natural product. Goal of the project was the synthesis of these fascinating molecules. Despite the interesting features of these natural products, only two research groups were actively working in this research field. During the course of the project, different approaches for the construction of bicyclic moiety have been developed as well as the construction of spiro system of elisabethin A. During the time span of the project, substantial progress has been made toward the synthesis of elisabethin A. 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.