The design and synthesis of highly potent epothilone B analogues and progress toward the total synthesis of Sinularia natural products.

摘要

As the first epothilone analogue has recently been approved for clinical use by the FDA, the epothilones stand on the verge of becoming the standard for chemotherapeutic care. A new batch of designed Epothilone B analogues has been synthesized that possess broad structural diversity on the heterocyclic sidechain and unrivaled biological activity against drug-susceptible and drug-resistant cell lines. The most potent epothilone analogues from this study are currently under development toward becoming clinical candidates.;Progress has been made toward the total synthesis of the complex and biologically active norcembranoid class of Sinularia natural products. Development of a convergent synthesis to a common, key intermediate has allowed for the near completion of Norcembranolide and Sinuleptolide. Within this synthetic strategy is the development of a novel rhodium-catalyzed macrocyclic ring closing reaction and a palladium-mediated acetylenic ketone rearrangement to 2,5-furans. This synthetic strategy provides access to the key intermediate of 8 complex natural products in the norcembrane, yonarane and dimeric-norcembrane families.