Development of an Enantioselective Synthesis of (−)-Euonyminol

Abstract

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-epieuonyminol or 8-epi-euonyminol. Our successful synthetic strategy provides a foundation to synthesize the more complex cathedulins.

Celastraceae sesquiterpene pyridyl ligands

“…Although the lactonisation reactions themselves are likely not inherently difficult, involving as they do primary (C13 and C14) and secondary (C3 and C8) alcohols, the main challenge will be constructing the dihydroagarofuran cores such that these specific positions can be reacted/activated selectively. This is a formidable endeavour given the complexity of the most prevalent core polyols, but the Herzon group has made important recent progress by preparing a selectively protected derivative of the nonahydroxylated dihydroagarofuran core (−)-euonyminol, 72,73 so we can probably expect exploration of this chemistry in the near future.…”

Total Synthesis of Euonymine and Euonyminol Octaacetate

“…In fact, among successful total syntheses of various dihydro-β-agarofurans, only two reports disclosed the total synthesis of 2 and others described the synthesis of less oxygenated congeners . White and colleagues transformed ( E )-pent-2-enal to racemic 2 over 19 total steps in 1995/1997, and Herzon and colleagues converted ( R )-carvone to enantiopure 2 over 40 total steps in 2021 . In both syntheses, euonyminol ( 3 ) was derivatized from the synthetic 2 by basic methanolysis.…”