Euphorbiaceae Diterpenes - Total Synthesis of Pl-3

Spurges of the Euphorbia plant family have a long tradition in the treatment of swellings, wart, and cancerous conditions and were common ingredients in ancient Roman and Greek herbal medicine. Numerous terpenes were isolated from Euphorbiaceae which display highly interesting biological properties. Pl-3, a highly functionalized diterpene with a five and twelve membered ring fragment, obtained from Euphorbia platyphyllos was found to inhibit the efflux pump activity of p-glycoprotein which makes the natural product an interesting and promising candidate as anti-cancer drug. A general and concise approach toward the Euphorbiaceae diterpene Pl-3 is presented. The stereo-chemical pattern of the target can easily be modified to grant access to structurally related diterpenes for biological activity testing and during the course of the project, derivatives will be prepared. Furthermore, a protocol for the synthesis of the five-membered ring fragment of Euphorbiaceae diterpenes is presented. Natural and unnatural occurring five- membered ring fragments will be synthesized to demonstrate the utility of this approach. Key steps in the preparation of the five-membered ring fragment are a ring-closing-metathesis, and a hydroboration reaction. The synthesis of the twelve-membered ring fragment takes advantage of the inherent stereochemistry of natural sugar derivatives. Chain elongation via Reformatsky reaction and installation of the olefin moiety completes the sequence. The fragments will be connected via Wittig, and metathesis reactions, respectively. Functional group manipulation completes the synthesis of the natural product.

The current project was concerned with the elaboration of synthetic strategies towards the preparation of Pl-3, a biologically intriguing natural product isolated from a member of the Euphorbiaceae plant family. Several spurges, as Euphorbiaceae plants are commonly referred to, have a long and rich tradition in traditional herbal folk medicine to cure various health conditions, including skin diseases, migraine, intestinal parasites, and warts. Over the last decades, phytochemists, have devoted considerable interest to the isolation of active ingredients from spurges and a vast number of biologically interesting and structurally complex natural products have been obtained.Pl-3 was isolated in 2003 from a Hungarian sample of the annual herbaceous plant Euphorbia platyphyllos. The natural product was identified to selectively inhibit a transporter protein which is responsible for the excretion of toxins from cells. As cancer cells are known to overexpress transporter proteins to reduce the cellular concentration of anticancer drugs, Pl-3 might serve as potential lead structure for the development of novel co-therapeutics for cancer chemotherapy.Pl-3 is characterized by a highly functionalized fused five- and twelve-membered ring system. During the course of the project, three independent routes towards the five-membered ring, and a concise approach towards the twelve-membered ring have been developed. The synthesis of these fragments has been designed to grant access to other structurally related diterpenes. Protocols developed for the preparation of Pl-3 have been applied to the synthesis of Pl-4, a related natural product with similar biological properties. Although the allocated time did not allow the completion of the synthetic work, the preparation of Pl-3 and Pl-4 are at an advanced stage. In addition to the synthetic progress, new methods have been developed, for example methods for the elaboration of quaternary centers. The selective lithition of a vinyl dibromide was elaborated and the advantage of latent symmetry in the synthesis of functionalized five-membered ring systems was discussed. These procedures will be of interest for synthetic chemists and will be explored in follow-up projects in the future.