Rychnovsky’s Formal Synthesis of Leucascandrolide A

1. Rychnovsky’sFormalSynthesis of Leucascandrolide A Presented by BriAnne Bentivegna March 19, 2013 University of Delaware Kopecky, D.J.; Rychnovsky, S.D. J. Am. Chem. Soc. 2001, 123, 8420

2. Scott D. Rychnovsky • 1981 - B.A. from University of California at Berkeley • 1986 - PH.D. from Columbia University • 1987 - NIH Postdoctoral Fellow at Harvard University • 1988 - Faculty member at the University of Minnesota • 1995 - Professor of Chemistry at the University of California – Irvine • Numerous Awards including Arthur C. Cope Scholar Award, Pfizer Research Award in Synthetic Organic Chemistry and National Science Foundation Presidential Young Investigator Award. • Associate Editor for The Journal of Organic Chemistry • Research interests include synthesis of rimocidin, phorboxazole A, epicalyxin F, and leucascandrolide A.

3. Leucascandrolide A • First isolated by Pietra and coworkers in 1996 from the calcareous sponge Leucascandra caveolata along the east coast of New Caledonia • Displays potent cytotoxic activity in vitro on human P388 (Leukemia) cancer cells as well as antifungal activity • Synthesized by several groups including the Rychnovsky, Leighton and Kozmin groups Dambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helvetica ChimicaActa. 1996, 79, 51

4. Retrosynthesis Yamaguchi-type Cyclization Aldol - Prins Coupling Noyori Hydrogenation Noyori Hydrogenation

5. Synthesis of Aldo-Prins Precursor #1 Noyori Hydrogenation

6. Synthesis of Aldo-Prins Precursor #2 Noyori Hydrogenation

7. Aldol-Prins Coupling Aldol - Prins Coupling

8. Synthesis of Leucascandrolide A Macrolide Leucascandrolide A Macrolide Yamaguchi-type Cyclization

9. Final Steps via Leighton Horner-Wadsworth-Emmons Leucascandrolide A!!! Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894

10. Conclusion • Leucascandrolide A Macrolide synthesized in 23 steps • Leucascandrolide A synthesized in 25 steps with the help of Leighton Questions?