Abstract
(+)-Ophiobolin A (1) was first isolated as a metabolite from the culture broth of the pathogenic plant fungus Ophiobolus miyabeanus, and from its absolute structure proof, the first naturally occurring sesterterpene was identified. Recent studies have revealed that 1 is cytotoxic to various cancer cell lines. 1 possesses eight stereogenic centers on the unique ring system including a spirocyclic ether. The A-ring incorporates three successive stereogenic centers including a chiral tertiary alcohol and two contiguous stereogenic centers at the cis-fused AB-ring junction. The CD-ring is a spirocyclic ether, possessing a total of five stereogenic centers, four of which are successive, as well as a quaternary stereogenic center at the trans-fused BC-ring junction. The potent bioactivities as well as the complex structure make 1 an attractive synthetic target. The total synthesis of 1 commenced with the construction of the spirocyclic CD-ring moiety. The spirocyclic CD-ring moiety was successfully constructed via the Lewis acid-promoted intramolecular Hosomi-Sakurai reaction. The CD-ring moiety was efficiently assembled with the A-ring fragment by the reaction reported by Utimoto et al. To the best of our knowledge, this is the first application of this coupling reaction to natural product synthesis. The first construction of the ophiobolin carbocyclic skeleton has been achieved by RCM, but it was sensitive to the substrate structure and use of the substrate with a less bulky protective group, such as benzyl ether, was crucial. Finally, the total synthesis of (+)-ophiobolin A has been achieved for the first time, via a convergent approach.
