Myers’ Synthesis of Dynemicin A

Andrew G. Myers

• 140 publications to date• (1981) B.S. at MIT – undergraduate research with W. R. Roush.• (1981-86) Graduate studies and brief post-doctoral work under E.J. Corey.• (1986) Began independent career – California Institute of Technology

– By 1994, became full professor.

• (1998) Moved to Harvard– 2007-2010, Served as chair of the chemistry department.

• Dr. Meyer’s research focuses on the synthesis of medically/biologically active compounds for human medicine development.

– Convergent, practical, and scalable syntheses.– Enediyne antibiotics synthesized: Neocarzinostatin chromophore, N1999A2, kedarcidin

chromophore, dynemicin A.– Methodology development.

Enediyne Antibiotics

calicheamicin

neocarzinostatin chromophore

kedarcidin chromophore

dynemicin A

esperamicin

Bioactivity – Intercalation and cleavage of DNA

-Enediyne antibiotics cleave both strands of DNA!-Irreversible damage-Anti-tumor activity

Previous work• Partial construction of dynemicin A (Z)-enediyne motif:

– Nicolaou Shreiber MagnusWender

• First full synthesis of dynemicin A analog:

– Shreiber

• First full synthesis of dynemicin A:

– Danishefsky

Initial strategies

Strategy 1

Strategy 2

Dynemicin A

Issue: Low yields likely because of highly reactive anthraquinone

Issue: Cyclization to form B ring was unsuccessful

Retrosynthesis

Part 1 – Construction of the A, B, C rings

22, 68 % 23, 15%

Attempted construction enediyne bridge

1,4-elimination

1,2-methoxy shift

Part 2 – Construction enediyne bridge

11:1 (29:30)

-Pseudoequatorial Me in 29 group leads to staggered product (thermodynamically favorable)

Model studies used to explain stereospecificity

Attempted addition of the D, E rings via an intermolecular Diels-Alder reaction – model studies

Diels-Alder approach Conjugate addition-enolate trapping

Unable to cyclize to anthraquinoneLow Yields

Part 3 – Addition of the D, E rings via an intermolecular Diels-Alder reaction

Model Diels-Alder reaction.

X-ray crystal structure of dynemicin analog 85

dynemicin analog 85

Analogs and 3-D structure

The Myers Group