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Organic Chemistry Highlights

Total Synthesis

Monday, June 4, 2018
Douglass F. Taber
University of Delaware

The Shenvi Synthesis of (-)-11-O-Debenzoyltashironin

There is a continuing interest in the polyoxygenated sesquiterpenes from Illicium sp. that promote neurite outgrowth. Building on their synthesis of jiadifenolide (Nature Chem. 2015, 7, 604. DOI: 10.1038/nchem.2283), Ryan A. Shenvi of Scripps/La Jolla devised (J. Am. Chem. Soc. 2017, 139, 9637. DOI: 10.1021/jacs.7b04206) an efficient synthesis of (-)-11-O-debenzoyltashironin (4). In both syntheses, the key step was the diastereoselective addition of the enantiomerically-pure lactone 1 to the prochiral lactone 2.

The preparation of 1 began with commercial citronellal (5). The aldehyde was converted to the 1,1-dibromide, that was then eliminated to give the volatile terminal alkyne 6. Ozonolysis followed by Mn-mediated cyclocarbonylation then delivered butenolide 1 as an inconsequential ~1:1 mixture of diastereomers. The preparation of 2 began with hydroxyacetone 7. Acylation with 8 gave the β-keto ester 9, that was cyclized to 2.

Deprotonation of 1 led to the enolate 10. Addition to 2 proceeded on the opposite face from the directing methyl group. The addition to 2 was also facially selective, leading, after intramolecular conjugate addition of the ketone enolate back onto the unsaturated lactone, to the tetracyclic dilactone 3. Four new stereogenic centers were set in place in the course of this condensation.

At this point, the synthesis diverged from the previous synthesis of jiadifenolide. Methylation of 3 gave 11. Saponification followed by decarboxylation and conversion of the free acid to the corresponding dimethylamide led to 12. Some molecular jiu-jitsu was then required to set the remaining two stereogenic centers. After dehydration to 13, the hydroxymethyl group was closed onto the ketone, constraining the geometry of the system so that α-hydroxylation of the amide proceeded to give 14. The amide was then converted to the lactone 15, so Mukaiyama hydration of the alkene would deliver the requisite diastereomer of the tertiary alcohol 16. Finally, acid-mediated cyclization completed the synthesis of (-)-11-O-debenzoyltashironin (4).

D. F. Taber, Org. Chem. Highlights 2018, June 4.