Monday, August 5, 2024
Douglass F. Taber
University of Delaware
The Yang Synthesis of Illisimonin A
Illisimonin A (3), isolated from the fruits of the Chinese "anise tree" Illicium simonsii, showed neuroprotective effects against oxygen-glucose deprivation (OGD)-induced cell injury in SH-SY5Y cells with an EC50 value of 27.72 μM. Ming Yang of Lanzhou University envisioned a route to 3 based on the Pd-catalyzed cyclization of the prochiral enol triflate 1 to the tricyclic diketone 2 (Angew. Chem. Int. Ed. 2023, 62, e202306367. DOI: 10.1002/anie.202306367).
The starting material for the preparation of 1 was 2-allylcyclopentan-1,3-dione (4). Alkylation with the allylic acetate 5 led to 6. The bis ketal could not be prepared from 6, but after ring-closing metathesis 7 formed smoothly. Oxidative cleavage led to the keto ester 8, that was cyclized, then acylated with propargyl chloroformate (9), and partially deketalized, to give 10. Pd-mediated rearrangement and coupling with p-methoxy phenol proceeded across the more open face of the six-membered ring, leading, after selective enol triflate formation, to 1 with high diastereocontrol.
Richard F. Heck showed that sodium formate was an effective hydride source in Pd-mediated bond formation. The conversion of 1 is presumably proceeding by way of an alkyl Pd hydride such as 11, with reductive elimination then leading to 2.
Mukaiyama hydration of 2 followed by retro-Dieckmann cleavage and deketalization led to the lactone 12. Deprotection followed by ketal formation gave 13, that was converted into the alkene 14 by coupling the derived enol triflate with AlMe3. Oxidation led to the α-keto lactone, that was deprotected to 15. Intramolecular aldol condensation of the transient diketone led to the diol 16, that was hydrated with high facial selectivity to illisimonin A (3).
It is instructive to compare this route to 3 with the two previous syntheses reported in these Highlights, by Rychnovsky ( 2020, August 31) and by Kalesse ( 2023, October 23).
D. F. Taber, Org. Chem. Highlights 2024, August 5.
URL: https://www.organic-chemistry.org/Highlights/2024/05August.shtm