Total Synthesis of (+)‐6‐epi‐Ophiobolin A

Abstract

The ophiobolin sesterterpenes are notable plant pathogens which have recently elicited significant chemical and biological attention because of their intriguing carbogenic frameworks, reactive functionalities, and emerging anticancer profiles. Reported herein is a total synthesis of (+)‐6‐epi‐ophiobolin A in 14 steps, a task which addresses construction of the synthetically challenging spirocyclic tetrahydrofuran motif as well as several other key stereochemical problems. This work demonstrates a streamlined synthetic platform to complex ophiobolins leveraging disparate termination modes of a radical polycyclization cascade for divergent elaboration and functionalization.

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

“…Following the extensive work they dedicated to (−)-6- epi -ophiobolin N ( 168 ), Maimone’s group reused one of the investigated cyclization conditions for the total synthesis of (+)-6- epi -ophiobolin A ( 173 ), which was then described in a 14-step strategy, starting from geraniol ( 169 ) [ 78 ]. Unlike compound 168 , the installation of stereogenic centers at C14 and C15 was not sought at the 8-5 cyclization stage of the strategy, since formation of the tetrasubstituted alkene provided an adequate precursor towards the tetrahydrofuran-ring formation.…”

Advances in polycyclization cascades in natural product synthesis

“…The group has recently reported a related radical cascade in the synthesis of 6epi-ophiobolin A. 49 Finally, the recent asymmetric total synthesis of hispidanin A (Scheme 21) by Liu and co-workers 50 phenylsilane-mediated radical polycyclization to form the transdecalin containing fragment 103 under substrate stereochemical control. The cascade is initiated by hydrogen atom transfer from an iron hydride species (generated in situ) to the more electron rich disubstituted alkene in 104.…”

Drophiobiolins A and B, Bioactive Ophiobolan Sestertepenoids Produced byDreschslera gigantea

“…All the results obtained on the cytotoxic activity of 3 and its congener have been recently reviewed . After we considered the very promising cytotoxic activity of ophiobolin A, its total synthesis was also recently realized in 14 steps …”

“…9 After we considered the very promising cytotoxic activity of ophiobolin A, its total synthesis was also recently realized in 14 steps. 23 The study in progress on the cytotoxic activity of ophiobolin A and particularly on its mode of action required its constant and continued production by fermentation using D. gigantea. From an in depth investigation of the mother liquors of 3 crystallization and of the other fractions obtanined during the purification steps, two new ophiobolins were isolated and named drophiobolins A and B (1 and 2).…”