Total Synthesis of the Antibiotic Kendomycin by Macrocyclization using Photo-Fries Rearrangement and Ring-Closing Metathesis

摘要

Kendomycin 1, (-)-TAN2162, an ansamycin isolated from different Streptomyces species, has been shown in studies over the last decade to be a potent endothelin receptor antagonist and antiosteoperotic compound with remarkable antibacterial and cytostatic activity. The challenging structure and diverse pharmacological profile of kendomycin has motivated us and, sometime later a number of other groups, to carry out studies towards its synthesis. To date, three total syntheses and one formal synthesis have been reported, along with a number of fragment preparations. The main problem for all the approaches has been the formation of the strained macrocyclic ansa-ring. For example, macrocycliza-tions were performed using C-glycosidation, Barbier-type organometallic addition, Prins reaction, and Horner-Wadsworth-Emmons olefination. Most strikingly, all attempts to achieve 13,14-macrocyclization by ring-closing metathesis (RCM) were plagued by low yields and formation of the undesired 13,14-Z-olefin. We tested alternative locations for RCM connections; however to our disappointment, both the 9,10- and the 19,20-positions proved to be unsuited. Nonetheless, we were still convinced that RCM should be a highly serviceable tool for ring closure.