Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, May 5, 2008
Douglass F. Taber
University of Delaware

The Rychnovsky Synthesis of Leucascandrolide A

The macrolactone leucascandrolide A (4), isolated from the calcareous sponge L. caveolata, has both cytotoxic and antifungal activity. The key step in the synthesis of 4 reported (J. Org. Chem. 2007, 72, 5784. DOI: 10.1021/jo070901r) by Scott D. Rychnovsky of the University of California, Irvine, was the stereoselective condensation of the aldehyde 1 with the allyl vinyl ether 2 to give 3.

The cyclic ether of 1 was assembled from the crotyl addition product 5. Tandem Ru-catalyzed metathesis / hydrogenation converted 5 to the lactone 6. Reduction of 6 to the lactol followed by activation as the acetate gave 7, axial-selective condensation of which with the enol ether 8 delivered the enone 9. Diastereoselective Itsuno-Corey reduction of 9 followed by protecting group exchange and oxidation then gave 1, containing four of the eight stereogenic centers of leucascandrolide A (4).

The vinyl ether 2 was readily prepared from the corresponding homoallylic alcohol. Condensation of 1 with 2 involved Lewis acid activation of the aldehyde, addition of the resulting carbocation to the vinyl ether, and cyclization with trapping by bromide ion. In this process, the other four of the eight stereogenic centers were assembled. Three of those centers were formed in the course of the reaction. While stereocontrol was not perfect, the route is pleasingly succinct, so practical quantities of diastereomerically pure 3 could be prepared.

To complete the synthesis, the secondary alcohol of 3 was methylated. Selective desilyation of the primary alcohol followed by oxidation and desilylation then set the stage for the Mitsunobu macrolactonization. The intermediates in the Mitsunobu reaction are such that the lactonization can proceed with either inversion of absolute configuration at the secondary center, or retention. While the usually-employed Ph3P gave the lactone with retention of absolute configuration, Bu3P led to clean inversion.

The last challenge was the establishment of the (Z) alkene of the side chain. This was accomplished using the Toru protocol. Coupling of the secondary bromide with the Cs salt 12 proceeded with inversion of absolute configuration, to give 13. The carboxylates of stronger acids were not sufficiently nucleophilic to displace the bromide. Aldol condensation of 13 with the aldehyde 14 gave a mixture of diastereomers, exposure of which to MsCl in pyridine delivered the requisite (Z) alkene 4.

D. F. Taber, Org. Chem. Highlights 2008, May 5.