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Organic Chemistry Highlights

Total Synthesis

Monday, October 3, 2022
Douglass F. Taber
University of Delaware

The Luo Synthesis of Grayanotoxin III

More than 25 grayanotoxin isoforms have been identified from rhododendron species, but grayanotoxin I and III are thought to be the principal toxic isoforms, leading to the well-known hazards of rhododendron honey. Tuoping Luo of Peking University devised a convergent synthesis of grayanotoxin III (3), based on the cyclization of 1 to 2 (J. Am. Chem. Soc. 2022, 144, 5268. DOI: 10.1021/jacs.2c01692).

The convergent assembly of 1 began with the enantioselective conjugate addition of 5 to 3-methyl cyclohexenone (4). Exposure to ICl gave 6, that was coupled with the organozinc reagent 7, leading to the silyl enol ether 8.

The preparation of the other half of 1 started from the prochiral diketone 9. Enantioselective reduction followed by acetylation gave 10, that was carried via treatment with the Vilsmeier reagent and acetal formation to 11. Squaramide-mediated Mukaiyama aldol addition of 8 gave 12, that was further cyclized to 13. Coupling with 14 led to 1.

The triflate derived from 1 was unstable, so it was taken directly into the cyclization. After quenching of the excess triflic anhydride with 2-propanol, heating with base led to 2, presumably by way of the bridgehead carbocation 15.

The skeleton of 2 bore an unneeded carbon atom. This was removed by singlet oxygenation, to give the α,β-unsaturated aldehyde, that was decarbonylated with an Ir catalyst to 16. Deconjugation of the enone to give the enol ether was then followed by oxidation, to give the epoxide 17. Lewis acid-mediated epoxide opening and 1,2-alkyl shift led, after proton loss and alkene equilibration, to 18, having the desired carbon skeleton. A series of oxidation steps then completed the synthesis of grayanotoxin III (3).

D. F. Taber, Org. Chem. Highlights 2022, October 3.