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Organic Chemistry Highlights

Total Synthesis

Monday, December 2, 2019
Douglass F. Taber
University of Delaware

The Snyder Synthesis of Chalcitrin

Chalcitrin (3) was isolated in trace amounts from the mushroom Chalciporus piperatus. Scott A. Snyder of the University of Chicago envisioned assembling the tricyclic core 2 of 3 by the N-heterocyclic carbene-mediated cyclization of the keto aldehyde 1 (J. Am. Chem. Soc. 2019, 141, 4515. DOI: 10.1021/jacs.8b12612).

The identical sidechains of 3 were prepared starting from commercial tetronic acid (4). Coupling with benzyl alcohol followed by iodination delivered 5, that was stannylated to give 6. Condensation of 6 with 7 followed by dehydration then completed the assembly of 8.

The preparation of 1 began with cyclopentenone (9). Conjugate addition of Me2PhSiLi followed by trapping of the resultant enolate with 10 led to 11, that was protected, then iodinated to give 12. Gold-catalyzed Conia ene cyclization of the derived silyl enol ether delivered the bicyclic 13. Ionization of the allylic leaving group followed by trapping of the carbocation with 14 from the more open face gave 15. Hydroboration followed by oxidation with NaBO3 and DMP then completed the assembly of the keto aldehyde 1.

The cyclization of 1 to 2 proceeded with remarkable facility. After oxidation of the alkyl silane to the corresponding alcohol, exposure to 17 delivered the enol ether 18. This was oxidized to the diketone, a vinylogous ester that could be hydrolyzed with LiOH to the triketone 19. The derived bromide 20 was coupled with 8, to give an intermediate that was debenzylated to Chalcitrin (3).

Although this work was carried out in the racemic series, the enantioselective conjugate addition of Me2PhSiLi to cyclopentenone (9) followed by enolate trapping has been reported by Hoveyda (J. Am. Chem. Soc. 2010, 132, 2898. DOI: 10.1021/ja910989n).

D. F. Taber, Org. Chem. Highlights 2019, December 2.