Enantioselective total synthesis of cyathin A3
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The cyathins are a unique group of diterpenoids produced by the bird’s nest fungi Cyathus helenae, C. africanus, and C. earlei. Several of the cyathins show strong antibiotic activity. More recently, several fungal metabolites with structures closely related to those of the cyathins have been found to be potent inducers of nerve growth factor (NGF) synthesis. The structural complexity and the exciting biological activity of the cyathane family of diterpenes have prompted our efforts to develop an efficient and general synthetic approach.To date, there have been seven total syntheses and six partial syntheses of cyathins. Most of these syntheses target allocyathin B2, which does not contain the common 6-7 trans ring fusion or the hydroxyl group within the seven member ring. Modifications of these routes to provide targets with these features have not been demonstrated and may be challenging. We have developed a concise asymmetric synthesis of cyathin A3, based on the enantioselective Diels-Alder reaction of quinone (106) and diene (105). Because the transformations of cyathin A3 into other cyathins are well documented, this synthesis provides a general approach to the cyathane diterpene family. In Section 2.2, the enantioselective Diels-Alder reaction of quinone 106 and diene 105 is presented. This reaction is effectively catalyzed by a carefully prepared Mikami catalyst. It was carried out on a preparative scale to give the chiral building block 108. The absolute configuration of the Diels-Alder adduct 108 was determined by NMR and X-ray analysis.In Sections 2.3-5, the enantioselective total synthesis of (-)-cyathin A3 is described. This approach features the successful oxymercuration ring opening, a newly developed in situ configuration inversion, a much improved intramolecular aldol reaction and a radical cyclization. Now envisioned in our laboratory is the development of a new access to cyathin A4, which is surmised to be possible via the intermediate prepared in this synthesis.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorWard, Dale E.
CommitteeMueller, Jens; Majewski, Marek; Dimmock, Jonathan R.; Clive, Derrick L. J.; Palmer, David
Copyright DateMay 2007