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Organic Chemistry Highlights

Total Synthesis

Monday, July 4, 2005
Douglass Taber
University of Delaware

Synthesis of (+)-Brasilenyne

(+)-Brasilenyne (3), isolated from the digestive gland of the sea hare Aplysia brasiliana, shows significant antifeedant activity. Scott Denmark of the University of Illinois has described (J. Am. Chem. Soc. 2004, 126, 12432. DOI: 10.1021/ja0466863) an elegant synthesis of 3, the key step of which is the Pd-mediated intramolecular coupling of 1 to give 2.

The enantiomerically-pure intermediate 1 was prepared from the dioxolanone 4, available in three steps from L-malic acid. Lewis acid-mediated homologation converted 4, a 4:1 mixture of diastereomers, into 5 as a single diastereomer. After establishment of the alkenyl iodide, it was necessary to maintain the lactone in its open form. A solution was found in the formation of the Weinreb amide. The final stereogenic center was established by Brown allylation of the derived aldehyde. The alkene metathesis to form 1 was carried out with the commercially-available Schrock Mo catalyst. The authors did not comment on the relative efficacy of alternative alkene metathesis catalysts.

With 1 in hand, the stage was set for the proposed Pd-mediated coupling. The authors were pleased to observe that the coupling conditions previously developed in the group worked efficiently with this much more complex substrate, leading to 2 as a single geometric isomer. After protection-deprotection and oxidation, homologation using the Corey protocol gave 10. Formation of the chloride proceeded with the expected clean inversion of absolute configuration, to give 3.

The least precedented transformation in this synthesis is the homologation of 4 to 5. This appears to be a general solution to a longstanding challenge, the construction of secondary-secondary ethers with absolute stereocontrol.

D. F. Taber, Org. Chem. Highlights 2005, July 4.