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Organic Chemistry Highlights

Total Synthesis

Monday, November 3, 2014
Douglass F. Taber
University of Delaware

The Trost Synthesis of (-)-Lasonolide A

A(-)-Lasonolide A (4), isolated from the Caribbean sponge Forcepia sp., shows remarkable anti-cancer activity in the NIH 60-cell screen. The central step in the synthesis of 4 reported (J. Am. Chem. Soc. 2014, 136, 88. DOI: 10.1021/ja411270d) by Barry M. Trost of Stanford University was the remarkably selective convergent Ru-mediated coupling of 1 with 2 to give 3.

To prepare 1, the authors took advantage of the under-utilized Cu-mediated addition of a Grignard reagent 6 to propargyl alcohol 5, to give 7. Coupling with the acetonide 8 followed by deprotection led to the phosphonium salt 9.

The other half of 1 was prepared from the acetonide 10 of the commodity chemical 1,1,1-tris(hydroxymethyl)ethane. Oxidation followed by Zn-catalyzed aldol addition of the ketone 11 led to the alcohol 12. Diastereoselective reduction followed by protection gave 13. Condensation with benzaldehyde proceeded with remarkable diastereoselection, setting the quaternary center of 14. Spontaneous intramolecular Michael addition proceeded under the conditions of the subsequent Horner-Emmons reaction, leading to the aldehyde 15. Wittig reaction with the phosponium salt 9 followed by deprotection completed the preparation of the alkyne 1.

The β-ketoester 18, prepared by the addition of 17 to 16, was prone to unwanted conjugation, and the terminal alkene was easily reduced under hydrogenation conditions. Enzymatic conditions were found to effect dynamic kinetic resolution and reduction, to give 19. The derived ketone 21 was reduced using the Corey organocatalyst, then hydrosilated, leading to 22. Under metathesis conditions, the product unsaturated aldehyde cyclized to 24. Homologation followed by allylation then completed the construction of 2.

Acetone was the solvent of choice for the coupling of 1 with 2. This led to the acetonide 3, that was hydrolyzed and protected to give 25. Yamaguchi macrolactonization followed by deprotection then delivered (-)-Lasonolide A (4). It is instructive to compare this work to the four previous total syntheses of 4, one of which (Synthesis of (-)-Blepharocalyxin D, (-)-Lasonolide A, and Attenol A 2007, November 26) we have previously highlighted.

D. F. Taber, Org. Chem. Highlights 2014, November 3.