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Organic Chemistry Highlights

Total Synthesis

Monday, August 1, 2022
Douglass F. Taber
University of Delaware

The Rawal Synthesis of Heilonine

Helionine (3) was isolated from the Chinese lily Fritillaria ussuriensis, used in traditional medicine. Viresh H. Rawal of the University of Chicago devised a convergent approach to 3, based on the cyclization of 1 to assemble the central benzene ring of 2 (J. Am. Chem. Soc. 2021, 143, 16394. DOI: 10.1021/jacs.1c08756).

The construction of the crystalline lactam 10 began with the Evans aldol addition of the acyl oxazolidinone 4 to the aldehyde 5 to give 6. This was carried on to the azide 7, that was cyclized, reduced and oxidized to the aldehyde 8. Conversion of the aldehyde to the alkyne with the Ohira-Bestmann reagent (9) then completed the preparation of 10.

The assembly of the bicyclic alkyne 1 began with the Diels-Alder cycloaddition of 11 with 12 to give 13. Again, application of the Ohira-Bestmann reagent led to the enol ether 14. Hydrolysis followed by re-silylation gave the alternative enol ether, that was condensed with methyl vinyl ketone to give a diketone that was cyclized to the enone 15. Protection of the enone then led to the tosylate 16, that was used to alkylate the linchpin reagent 17. Hydrolysis and exposure to Ph3P/CBr4 gave a bromide that was coupled with 10 to complete the preparation of 1.

The Rh-catalyzed cyclization of 1 probably proceeded via initial coupling of the two proximal alkynes to give an intermediate such as 18. That put the third alkyne within reach, leading to 2.

The lactam 2 was methylated, and the ketone was deprotected, leading to the conjugated enone, that was converted to the enol acetate 19. Epoxidation, hydrolysis and β-elimination led to an allylic alcohol, that on acid-mediated enolization gave the corresponding 1,4-diketone. Reduction completed the synthesis of helionine (3).

D. F. Taber, Org. Chem. Highlights 2022, August 1.