Synthetic efforts on the road to marine natural products bearing 4-O-2,3,4,6-tetrasubstituted THPs: an update

A review covering the synthetic efforts directed to miyakolide, polycavernoside A, lasonolide A, clavosolide A and madeirolide A. They belong to the unique families of marine macrolides bearing 4-O-2,3,4,6 tetrasubstituted THPs.

The Trost Synthesis of (−)-Lasonolide A

(−)-Lasonolide A 4, isolated from the Caribbean sponge Forcepia sp., showed remarkable anticancer activity in the NIH 60-cell screen. The central step in the syn­thesis of 4 reported (J. Am. Chem. Soc. 2014, 136, 88) 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 underutilized 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 phosphonium 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, from coupling with 20 was reduced using the Corey organocatalyst, then hydrosilated, leading to 22. Under metathesis with 23, 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 (Org. Highlights November 26, 2007) we have previously highlighted.