The document summarizes the isolation, biological activity, and total synthesis of discodermolide, a compound isolated from the marine sponge Discodermia dissoluta in 1990 that shows potent immunosuppressive, antifungal, and microtubule stabilization properties. Discodermolide is a highly potent anticancer agent that is effective against multi-drug resistant cell lines and has high water solubility compared to other microtubule stabilization agents like Taxol. The document reviews the history of discodermolide synthesis from the first total synthesis in 1993 to phase I clinical trials by Novartis in 2003.

1. TOTAL SYNTHESIS OF
DISCODERMOLIDE
有機合成化学特論 発表資料
2012-01-06 有末 芳 (M1)

2. Isolation:
Gunasekera (1990)
Yield:
0.002wt% (7 mg/454 g of sponge)
Biological Activity:
Discodermia dissoluta
Immunosuppression
Antifungal
Microtubule Stabilization (MTS agent)
Important Profiles:
• Acts more faster and powerful than any other MTS agents.
Cancer Cell and
• Effective against multi-drug (include Taxol) resistant cell lines. Its Apoptosis
• High water solubility (100-fold greater than Taxol)
• Unique action mechanism, etc…
Very attracted compound !!!
Isolation: JOC 1990, 55, 4912. For action of mechanism, see: ACIE 1998, 37, 2014.

3. 1990 Gunasekera Isolation
1993 Schreiber First total synthesis ((–)-form)
Established absolute configuration
1994 Schreiber First natural (+)-enantiomer synthesis
1995 Smith (–)
1997 Myles (–)
1998 Marshall (+)
1999 Smith Gram-scale synthesis
2000 Paterson Novel approach
2002 Paterson 2nd generation
2003 Smith 2nd generation
2003 Novartis Process synthesis
Phase I clinical trials
2005 Panek (+)

12. What are most effective?
1. Aldol
2. Allylboronate/allylborane addition to aldehyde
3. Ireland-Claisen
4. Diels-Alder
Marshall’s concept: chiral allenylmetal methodology (variant of 2)
JOC 1998, 63, 817

13. JOC 1998, 63, 7885

14. Model for selectivity: JOC 1995, 60, 5556.

17. Chelation model: JACS 1983, 105, 4833