The Keck Synthesis of Epothilone

The total synthesis of Epothilone B 4, the first natural product (with Epothilone A) to show the same microtubule-stabilizing activity as paclitaxel (Taxol ), 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) by Gary E. Keck of the University of Utah was based in large part on the stereoselective allyl stannane additions (e.g. 1 + 2 3) that his group originated. 

The allyl staimane 2 was prepared fi om the acid chloride 5. Exposure of 5 to Et,N generated the ketene, that was homologated with the phosphorane 6 to give the aUene ester 7. Cu-mediated conjugate addition of the stannyhnethyl anion 8 then delivered 2. 

The silyloxy 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 horane 12 to the derived aldehyde 11 also proceeded with high diastereocontrol. 

The other component of 4 was prepared from the aldehyde 14. Enantioselective aUyla-tion, by the method the authors developed, delivered the alcohol 16. The Z trisubstituted 

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. 

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