synthesis of discodermolides useful for investigating microtubule binding and stabilization

Synthesis of Discodermolides Useful for Investigating Microtubule Binding and

StabilizationMelissa G. Morris

CHEM 635February 12, 2013

Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080

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

History1990–isolated by Gunasekera and co-workers at the Harbor

Branch Oceranographic Institute from the deep-sea marine sponge Discodermolide dissoluta

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

Retro-synthesis

• 2 = C-C7• 3 = C9-C15• 4 = C16-C24

Forward Synthesis Synthesis of C1-C7

Synthesis of C9-C15

Forward Synthesis Cont. Synthesis of C16-C24

Combining the Fragments

Reduction of acetylene was too problematic in the presence of the terminal diene

C16-C24

C9-C15

Revision of Coupling

…doesn’t work!

The Final Step…

Final Step Revised

Stereochemistry

His original total synthesize provided: ([a]20

D = -13.0(c = 0.6, methanol)).

The current synthesis provided: ([a]20

D = +14.0 (C = 0.6, methanol)), which was obtained via biological characterization

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 in vivo

Why: Disocdermolide comprises numerous biological properties: Immunisuppressive Antiproliferative/antimitotic Potent microtubule-stabilizing agent

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

Structural Variants Cont.

32 and 35 were not active in vivo, suggesting that the full length of Discodermolide was necessary for receptor recognition

Binding Reagent Syntheses

Binding Reagents Cont.

Binding Reagents Cont.

Substrate Product R1 R2 IC50

27b50a

a-PhS S-Me 6nM

27a50b

a-PhS S-Me 4nM

26b51

b-PhS H 4nM

Summary of Reagents and Activities

no. IC50a(nM) no. IC50

a (nM)

1 1a 6 8 372 31 10 9 45 703 1c 300 10 50a 64 1b 11 50b 45 32 12 51 46 35 13 597 36 70

Final Biological Assay Results

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

(Extra) Synthesis of 59