Stereocontrolled Total Synthesis of ( + )-Vinblastine

1. Stereocontrolled Total Synthesis of (+)-Vinblastine Satoshi Yokoshima, Toshihiro Ueda, Satoshi Kobayashi, Ayato Sato, Takeshi Kuboyama, Hidetoshi Tokuyama, and Tohru Fukuyama Presented By William Reid 2/26/13

2. (+)-Vinblastine • Isolated fromCatharanthusroseus • Widely known agent for chemotherapy • Binds tubulin • Only four previous syntheses

3. (+)-Vinblastine • Isolated fromCatharanthusroseus • Widely known agent for chemotherapy • Binds tubulin • Only four previous syntheses • Required natural sources of (-)-vindoline

4. (+)-Vinblastine • Isolated fromCatharanthusroseus • Widely known agent for chemotherapy • Binds tubulin • Only four previous syntheses • Required natural sources of (-)-vindoline • Stereochemistry of C18

5. Goals • Prepare an efficient route for the synthesis of (-)-vindoline • Improvement over biomimetic syntheses • Control the stereocehemistry of C18 • Eleven membered ring intermediate Schill, G.; Priester, C. U.; Windho¨vel, U. F.; Fritz, H. Tetrahedron 1987, 43, 3765.

6. Retrosynthesis

7. Retrosynthesis2(-)-vindoline

8. Scheme 2(-)-vindoline

9. Scheme 3

10. Scheme 3

11. Scheme 3 15

12. Scheme 3 (-)-vindoline Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett2000, 883

13. Scheme 4(The Upper Half)

14. Scheme 5

15. Scheme 6 (+)-vinblastine

16. Conclusion • Successfully synthesized (-)-vindoline • Successfully synthesized 3 in 2% yield via a radical cyclization of o-alkenylthioanilide • Successfully synthesized (+)-vinblastine • Correct stereochemistry • Convergence

17. Questions??