Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, July 6, 2009
Douglass F. Taber
University of Delaware

The Keck Synthesis of Epothilone B

The total synthesis of Epothilone B (4), the first natural product (with Epothilone A) to show the same microtubule-stabilizing activity as paclitaxel (TaxolŽ), has attracted a great deal of attention since that activity was first reported in 1995. The total synthesis of 4 devised (J. Org. Chem. 2008, 73, 9675. DOI: 10.1021/jo802215v) by Gary E. Keck of the University of Utah was based in large part on the stereoselective allyl stannane additions (e.g. 1 + 23) that his group originated.

The allyl stannane 2 was prepared from the acid chloride 5. Exposure of 5 to Et3N generated the ketene, that was homologated with the phosphorane 6 to give the allene ester 7. Cu-mediated conjugate addition of the stannylmethyl anion 8 then delivered 2.

The benzyloxy aldehyde 1 was prepared from the ester 9 by reduction with Dibal. Felkin-controlled 1,2-addition of the allyl stannane 2 established the relative configuration of the secondary alcohol of 3, that was then used to control the relative configuration of the new alcohol in 10. Addition of the crotyl borane 12 to the derived aldehyde 11 also proceeded with high diastereocontrol.

The other component of 4 was prepared from the aldehyde 14. Enantioselective allylation, by the method the authors developed, delivered the alcohol 16. The Z trisubstituted alkene was then assembled by condensing the aldehyde 17 with the phosphorane 18. Dibal reduction of the product lactone 19 gave a diol, the allylic alcohol of which was selectively converted to the chloride with the Corey-Kim reagent. Hydride reduction then delivered the desired homoallylic alcohol, that was converted to the phosphonium salt 21. Condensation of 21 with 13 gave the diene, that was carried on to Epothilone B (4).

The synthesis of Epothilone B (4) as originally conceived by the authors depended on ring-closing metathesis of the triene 22. They prepared 22, but on exposure to the second-generation Grubbs catalyst it was converted only to 23. The authors concluded that the trans acetonide kept 22 in a conformation that did not allow the desired macrocyclization.

D. F. Taber, Org. Chem. Highlights 2009, July 6.