A Formal Total Synthesis of Eleutherobin Through an Unprecedented Kinetically Controlled Ring-Closing-Metathesis Reaction of a Densely Functionalized Diene

摘要

Sarcodictyins A (1 a) and B (1 b) were isolated in 1987 by Pietra and co-workers from the Mediterranean stoloniferan coral Sarcodictyon roseum.[1] Their antitumor activity was recognized about a decade later, and their taxol-like mechanism of action was discovered in 1996.[2] In the meantime, the diterpene glycoside eleutherobin (2) was reported by Fenical et al. from an Eleutherobia species of Australian soft coral, accompanied by disclosure of its potent cytotoxicity in 1995.[3] Two years later, eleutherobin was shown to act similarly to the sarcodictyins, effecting mitotic arrest through tubulin polymerization.[4] Both sarcodictyins and eleutherobin (the eleutheside family of microtubule-stabilizing drugs) are characterized by an activity profile different from that of taxol; they are active against taxol-resistant tumor cell lines and therefore hold potential as second-generation microtubule-stabilizing anticancer agents.[4], [5] The scarce availability of 1 and 2 from natural sources makes their total syntheses vital for further biological investigations.[5] To date, sarcodictyin A and B have been synthesized successfully by Nicolaou et al.,[6] who have also exploited a similar route to eleutherobin.[7] A subsequent report by Danishefsky and co-workers details an elegant alternative access to eleutherobin.[8] A number of synthetic approaches to the eleutheside natural products and syntheses of simplified analogues have also been described.