有機合成化学特論 発表資料

2012-01-06 有末 芳 (M1)

TOTAL SYNTHESIS OF

DISCODERMOLIDE

Discodermia dissoluta

Isolation:

Gunasekera (1990)

Yield:

0.002wt% (7 mg/454 g of sponge)

Biological Activity:

Immunosuppression

Antifungal

Microtubule Stabilization (MTS agent)

Important Profiles:

• Acts more faster and powerful than any other MTS agents.

• Effective against multi-drug (include Taxol) resistant cell lines.

• High water solubility (100-fold greater than Taxol)

• Unique action mechanism, etc…

Cancer Cell and

Its Apoptosis

Isolation: JOC 1990, 55, 4912. For action of mechanism, see: ACIE 1998, 37, 2014.

Very attracted compound !!!

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 (+)

1. Aldol

2. Allylboronate/allylborane addition to aldehyde

3. Ireland-Claisen

4. Diels-Alder

Marshall’s concept: chiral allenylmetal methodology (variant of 2)

What are most effective?

JOC 1998, 63, 817

JOC 1998, 63, 7885

Model for selectivity: JOC 1995, 60, 5556.

Chelation model: JACS 1983, 105, 4833