Total Synthesis of Discodermolides: Investigating Microtubule Binding

1. Synthesis of Discodermolides Useful for Investigating Microtubule Binding and Stabilization Melissa G. Morris CHEM 635 February 12, 2013 Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080

2. Stuart L. Schreiber, Ph.D. • Born February 6, 1956 • B.A. in chemistry from UVA, 1977 • Ph.D. from Harvard University • Joined Yale University faculty in 1981 • Promoted to associate professor in 1984 • Full Professor in 1986 • Retuned to Harvard in 1988–present • Morris Loeb Professor of Chemistry • and Biology • Director of Chemistry Biology • A Founding Member of the Broad • Institute of Harvard and MIT. • His research is focused in chemical biology • >460 publications

3. History • 1990–isolated by Gunasekera and co-workers at the Harbor Branch Oceranographic Institute from the deep-sea marine sponge Discodermolidedissoluta • 1993–Schreiber and co-workers reported the first total synthesis of Discodermolide, but unfortunately the unantural antipode, (-)-Discodermolide • They also determined the absolute stereochemistry, something Gunasekera was unable to determine

4. Retro-synthesis • 2 = C-C7 • 3 = C9-C15 • 4 = C16-C24

5. Forward Synthesis Synthesis of C1-C7 Synthesis of C9-C15

6. Forward Synthesis Cont. Synthesis of C16-C24

7. Combining the Fragments C9-C15 Reduction of acetylene was too problematic in the presence of the terminal diene C16-C24

8. Revision of Coupling

9. The Final Step… …doesn’t work!

10. Final Step Revised

11. Stereochemistry His original total synthesize provided: ([a]20D = -13.0(c = 0.6, methanol)). The current synthesis provided: ([a]20D = +14.0 (C = 0.6, methanol)), which was obtained via biological characterization

12. Synthesizing Derivatives for Biological Studies • Purpose: To further characterize the interactions between Discodermolide and its receptor • How: Synthesize an array of targets that can be analyzed when subjected invivo • Why:Disocdermolidecomprises numerous biological properties: • Immunisuppressive • Antiproliferative/antimitotic • Potent microtubule-stabilizing agent

13. Structural Variants for Studying Interactions with Discodermolide Receptor • Before these variants were made, truncated version of Discodermolide were tested to see if the full length is needed for receptor recognition

14. Structural Variants Cont. • 32 and 35 were not active in vivo, suggesting that the full length of Discodermolide was necessary for receptor recognition

15. Binding Reagent Syntheses

16. Binding Reagents Cont.

17. Binding Reagents Cont.

18. Summary of Reagents and Activities Final Biological Assay Results

19. Conclusion A total synthesis of (+)-Discodermolide in 36 steps, with an overal yield of 4.3% over 24 steps (the longest linear sequence) Discodermolide remains the most potent natural promoter of tubulin assembly

20. (Extra) Synthesis of 59