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Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade

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Science  27 May 2016:
Vol. 352, Issue 6289, pp. 1078-1082
DOI: 10.1126/science.aaf6742

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A radical route to ophiobolin rings

Chemical ring-closing cascades resemble molecular yoga. One reactive site on a linear precursor can pull the whole molecule into a remarkably complex polycyclic arrangement. Cyclase enzymes rely on substantial internal scaffolding to guide this process during the biosynthesis of the ophiobolin sesterterpene frameworks, which comprise two pentagons sharing edges with an octagon. Brill et al. now show that the same motif is accessible abiotically by tweaking the cascade mechanism to rely on neutral radical intermediates in place of the positively charged activated sites in the biosynthetic pathways.

Science, this issue p. 1078

Abstract

Cyclase enzymes weave simple polyprenyl chains into the elaborate polycyclic ring systems of terpenes, a sequence that is often difficult to emulate under abiotic conditions. Here we report a disparate synthetic approach to complex terpenes whereby simple prenyl-derived chains are cyclized using radical, rather than cationic, reaction pathways. This strategy allowed us to efficiently forge the intricate 5-8-5 fused ring systems found in numerous complex natural product classes and also enabled a nine-step total synthesis of (–)-6-epi-ophiobolin N, a member of the large family of cytotoxic ophiobolin sesterterpenes. A small-molecule thiol catalyst was found to override the inherent diastereoselectivity observed during a reductive radical cascade cyclization process. This work lays the foundation for efficient synthesis of terpenoid ring systems of interest in medicinal research, particularly those that have been historically challenging to access.

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