Syntheses of (+)-Antrodiellin B, (−)-Hypnophilin and (−)-Coriolin and Strained 5/5/5 and 5/6/4 Skeletons via [5+2+1]/Epoxidation/Transannular Radical Cyclization


Nature produces many molecules (so-called natural products) containing compact scaffolds such as cis-anti-cis-configurated 5/5/5 and 5/6/4 tricycles. But other molecules with more strained structures, such as trans-anti-cis-configurated 5/5/5 tricycles have been rarely found in nature. Accessing all these natural and non-natural molecules will strengthen the power of organic synthesis and benefit many fields such as medicinal chemistry, chemical biology that are heavily dependent on the available quantity of new/important molecules. Herein, we report a new strategy to synthesize molecules with cis-anti-cis-configurated 5/5/5 tricycles, 5/6/4 tricycles and trans-anti-cis-configurated 5/5/5 tricyclic skeletons by [5+2+1]/epoxidation/transannular radical cyclization strategy, where challenging cis and trans 5/8 bicycles with both ene and carbonyl functional groups were accessed by Rh-catalyzed [5+2+1] reaction of ene-vinylcyclopropanes and carbon monoxide, followed by epoxidation of the double bond in the 5/8 bicycles, and Ti(III) mediated epoxide/carbonyl cyclization to build target skeletons. This strategy was further applied to the first total synthesis of (+)-antrodiellin B, the asymmetric total synthesis of (−)-hypnophilin and formal synthesis of (−)-coriolin with cis-anti-cis configurated 5/5/5 skeleton (both hypnophilin and coriolin are highly oxidized and have significant biological activities).


Supplementary material

Supporting Information
All the characterization data, experimental protocols and DFT studies are provided in Supplementary Information.