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Organic Chemistry Highlights

Total Synthesis

Monday, January 2, 2017
Douglass F. Taber
University of Delaware

The Siegel Synthesis of Eupalinilide E

Eupalinilide A (3), isolated from the East Asian herbaceous perennial Eupatorium lindleyanum, has the remarkable property of inhibiting hematopoietic stem/progenitor cell differentiation in cell culture, driving progenitor expansion. Dionicio Siegel of the University of California, San Diego envisioned (J. Am. Chem. Soc. 2016, 138, 6068. DOI: 10.1021/jacs.6b03055) assembling the carbon skeleton of 3 by the Lewis acid-mediated cyclization of 1 to 2.

The construction of 1 with control of relative and absolute configuration was a challenge. The starting point was the bromination of carvone 4 to 5, followed by Favorskii rearrangement to the volatile lactone 6, as previously reported by Wolinsky. Reduction followed by dehydration converted 6 to 7.

The crucial side-chain stereochemical control was achieved by the addition of vinyl lithium to the aldehyde 8, that proceeded with remarkable diastereocontrol to give, after ether construction, the triene 9. Pd-catalyzed borylative cyclization of 9, according to the Cárdenas protocol, followed by oxidative work-up, completed the assembly of the alcohol 10.

As hoped, oxidation of the alcohol 10 followed by Lewis acid-mediated cyclization delivered the tricyclic 2, again with remarkable diastereocontrol. Esterification of 2 with tiglic acid (11) by the Yamaguchi procedure then led to 12.

The ester 12 was readily desilylated on exposure to trifluoroacetic acid. The challenge was the selective oxidation of the desilylated intermediate to the keto lactone 13. Eventually it was found that CrO3/3,5-dimethylpyrazole functioned sufficiently well. Modified Luche reduction and selective epoxidation led to 14, and that was opened with chloride to complete the synthesis of 3.

The late-stage oxidation of 12 to 13 made it possible to bring very lightly functionalized intermediates through the early stages, significantly simplifying the synthesis. Just from this first success, the authors reported the preparation of 466 mg of the natural product. Since it is active at 600 nM, that is already a substantial supply.

D. F. Taber, Org. Chem. Highlights 2017, January 2.