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Organic Chemistry Highlights

Total Synthesis

Monday, November 4, 2019
Douglass F. Taber
University of Delaware

The Fürstner Synthesis of Sinulariadiolide

Sinulariadiolide (3) was isolated from the Okinawan soft coral Sinularia in 1996. Alois Fürstner of the Max-Planck-Institut für Kohlenforschung envisioned the preparation of 3 by alkyne metathesis of 1 to 2, followed by transannular ring closure (J. Am. Chem. Soc. 2019, 141, 805. DOI: 10.1021/jacs.8b12185)

The preparation of the alcohol portion of ester 1 began with geranic acid (4). Alkylative esterification followed by ozonolysis led to 5, that was coupled with 6 to give 7. Usually with such oxidations the N-O bond is cleaved immediately, but in this case the authors found that the tetramethylpiperidyl group served well to protect the alcohol, promoting stereoselective addition of 8 to give, after silylation, the alkyne 9. Net enantioselective conjugate hydroxylation then completed the assembly of 10. Through the algebra of sequential enantioselective transformation, the diastereomer 10 was delivered in high ee.

The acid portion of ester 1 was prepared from commercial carvone (11). Epoxidation followed by Eschenmoser fragmentation led to 12, that was oxidized with sodium chlorite in the presence of the acid scavenger 13 to give 14.

The combination of the two fragments was effected by first acylating 15 with 14. On warming, this led to the in situ generation of the acyl ketene, that coupled with 10 to give 16. In preparation for the Mo-catalyzed metathesis, the β-ketoester was masked as the enol acetate and the silyl ether was deprotected, to give 1.

Following metathesis the durable TMP group was removed, to give 1. Hydroxyl-directed stannylation followed by methoxycarbonylation led to 18. Activation of the diol as the cyclic carbonate then set the stage for a remarkable series of transformations. Methoxide removal of the acetyl group generated an enolate that added in an intramolecular sense to the unsaturated ester, the constraints of the ring conformation directing the relative configuration. β-Elimination from the newly-formed enolate led to the unsaturated lactone, that underwent diastereoselective conjugate addition of methoxide. The methyl ether was then deprotected in the presence of 13 to give sinulariadiolide (3).

D. F. Taber, Org. Chem. Highlights 2019, November 4.