Chang S, Hur S, Britton R * Simon Fraser University, Burnaby, Canada
Total Synthesis of Ascospiroketal A Through a Ag
I-Promoted Cyclization Cascade.
Angew. Chem. Int. Ed. 2015;
54: 211-214
Key words
ascospiroketal A - structure elucidation - oxetanes - silver - spirocyclization -
cascade reaction
Significance
Ascospiroketal A was isolated in 2007 from the marine fungus Ascochyta salicorniae. This natural product is characterized by a spiroketal that is part of a fused tricyclic
system. While the relative configuration of the spirocyclic core could be elucidated
by NOESY spectroscopy, no sterochemical information for the side chain could be obtained.
Britton and co-workers present a synthetic strategy, which allowed not only for the
efficient construction of the core fragment but also for a late-stage introduction
of the contested side chain. Their efforts culminated not only in the first total
synthesis of ascospiroketal A but also in the establishment of the C15-C2′-C3′ stereochemistry.
Comment
The synthesis commenced with the preparation of enantioenriched aldehyde D from hydroxyoxetane A. A diastereoselective aldol reaction with ketone F gave cyclization precursor G. Extending a method developed in their laboratory (Org. Lett. 2012, 14, 5844), Britton and co-workers exposed G to a combination of Ag2O and AgBF4. Ketal H is presumed to be formed first, followed by nucleophilc opening of the oxetane, yielding
a 1:1 mixture of I and J. The complete diastereoselective oxetane opening might be attributed to the chelation
of silver(I). Notably, the undesired isomer I could be epimerized to J. After several isomeric side chains were attached, the authors found that ascospiroketal
A possesses the configuration as depicted above.
