Development of an Enantioselective Synthesis of (-)-Euonyminol

We detail the development of the first enantioselective synthetic route to euonyminol (1), the most heavily oxidized member of the dihydro-β-agarofuran sesquiterpenes and the nucleus of the macrocyclic alkaloids known as the cathedulins. Key steps in the synthetic sequence include a novel, formal oxyalkylation reaction of an allylic alcohol by [3 + 2] cycloaddition; a tandem lactonization-epoxide opening reaction to form the trans-C2-C3 vicinal diol residue; and a late-stage diastereoselective trimethylaluminum-mediated α-ketol rearrangement. We report an improved synthesis of the advanced unsaturated ketone intermediate 64 by means of a 6-endo-dig radical cyclization of the enyne 42. This strategy nearly doubled the yield through the intermediate steps in the synthesis and avoided a problematic inversion of stereochemistry required in the first-generation approach. Computational studies suggest that the mechanism of this transformation proceeds via a direct 6-endo-trig cyclization, although a competing 5-exo-trig cyclization, followed by a rearrangement, is also energetically viable. We also detail the challenges associated with manipulating the oxidation state of late-stage intermediates, which may inform efforts to access other derivatives such as 9-epi-euonyminol or 8-epi-euonyminol. Our successful synthetic strategy provides a foundation to synthesize the more complex cathedulins.